NRLF 


B   M    210   3DD 


MEDICAL 


Dr.  Howard  Herrington 

Memorial 


^<Z/7-«^-*-- 


f 


INFECTION    AND     IMMUNITY 


By 


VICTOR   C.  VAUGHAN,  M.D. 
ANN  ARBOR,  MICH. 


CHICAGO 

AMERICAN  MEDICAL  ASSOCIATION 
1915 


COPYRIGHT,  1915 

BY    THE 

AMERICAN  MEDICAL  ASSOCIATION 


19)5' 


This  monograph  is  a  part  of  the  Commemoration  Volume,  issued 
by  the  American  Medical  Association  at  its  meeting  in  San  Francisco, 
June  22  to  26,  1915,  as  a  tribute  to  the  medical  sciences,  which  made 
possible  the  building  of  the  Panama  Canal  and  the  Panama  Pacific 
Exposition. 


31727 


FOREWORD 

The  development  of  modern  medicine,  its  influence  on  civilization, 
and  its  role  in  the  advancement  of  the  welfare  of  the  nation  are  mat- 
ters which  concern  us  all.  While  our  lives  are  short  and  we  are  soon 
to  pass  away,  our  children  and  their  descendants  will  possess  and 
occupy  the  land, — at  least  we  hope  that  this  may  be  true.  No  nation 
can  be  great  so  long  as  disease  prevails  widely  among  any  classes. 
Modern  medicine  has  become  largely  a  social  service.  Preventive 
medicine  is  the  keystone  of  the  triumphal  arch  of  modern  civilization. 
Displace  it  and  the  whole  structure  will  fall.  Widespread  epidemics 
lead  to  national  decay.  Infection  has  overthrown  nations  and  has 
blotted  out  civilizations  in  the  past.  We  are  aware  of  the  fact  that 
the  future  of  this  country  does  not  depend  wholly  on  the  medical  man, 
but  he  should  be  ready  at  all  times  to  do  his  part  in  assisting  in  the 
progress  of  the  nation.  Medicine  consists  of  those  facts,  gathered 
from  the  various  sciences,  which  can  be  utilized  in  the  prevention  or 
cure  of  disease.  That  nation  which  does  not  encourage  scientific  inves- 
tigation, must  fall  into  the  rear.  It  is,  therefore,  the  duty  of  the  state 
to  favor  research  medicine.  Every  physician  who  treats  an  infectious 
disease  renders  a  service  to  the  individual  under  his  treatment,  and  at 
the  same  time  he  renders  a  greater  service  to  the  community  in  pre- 
venting the  spread  of  the  disease. 

The  present  volume  is  an  incomplete  and  imperfect  statement  of 
what  medicine  has  done,  is  doing,  and  an  indication  of  what  it  may  do 
for  the  common  good.  The  attempt  has  been  made  to  present  these 
facts  in  non-technical  verbiage  so  that  any  intelligent  citizen  may 
read,  comprehend,  and  appreciate  them.  The  medical  profession  feels 
that  it  has  a  patriotic  duty  to  perform  in  the  advancement  of  the  best 
interests  of  the  people.  It  offers  its  services,  and  begs  an  intelligent 
appreciation  of  what  it  has  done,  is  doing,  and  may  do. 


CONTENTS 


Infection     17 

Historical    Introduction     19 

Bacteria     27 

Avenues   of    Infection 35 

Tuberculosis    39 

Leprosy     51 

Asiatic  Cholera    57 

Typhoid    Fever     65 

Anthrax    77 

Dysentery    87 

Typhus  Fever   93 

Plague     i Ill 

Symptomatic  Anthrax   127 

Malignant  Edema   131 

Gas   Phlegmon    132 

Glanders    133 

Botulism — Sausage  Poisoning  137 

Malta  Fever    139 

Pneumonia   143 

Tetanus     149 

Streptococcic  Infection    153 

Staphylococcic  Infection   161 

Diphtheria    167 

Immunity    175 

Introduction    177 

Phagocytosis    183 

Specific  Precipitins   197 

Agglutination    201 

Opsonins     207 

Germicidal    Sera    213 

The  General  Principles  and  Mechanism  of  Infection  and  Immunity 223 

The  Index   . 


CHAPTER    I 


INTRODUCTION 

The  purpose  of  this  writing  is  to  state  the  essential  facts  of  infec- 
tion and  immunity  accurately  and  simply,  so  that  they  may  be  under- 
stood by  the  intelligent,  non-professional  man.  The  reduction  and 
ultimate  eradication  of  unnecessary  disease  and  the  consequent  pro- 
longation of  life  with  improved  health  constitute  a  patriotic  obligation 
which  every  citizen  should  strive  to  appreciate  and  to  do  his  part  in 
its  performance. 

The  further  developments  of  medicine,  both  curative  and  pre- 
ventive, depend  on  scientific  investigations.  The  public  is  the  bene- 
ficiary and  should  in  every  way  encourage  medical  research.  By  the 
application  of  discoveries  already  made,  the  burden  of  disease  has 
been  lightened,  sickness  has  become  less  frequent  and  less  prolonged, 
a  greater  degree  of  health  has  been  secured,  the  efficiency  of  the 
individual  and  of  the  nation  has  been  increased,  and  life  has  been 
lengthened  and  made  more  enjoyable.  The  Federal  government  and 
the  states  should  sustain  and  promote  scientific  research.  That  gov- 
ernment is  the  best  which  secures  for  its  citizens  the  greatest  freedom 
from  disease,  the  highest  degree  of  health  and  the  longest  life,  and  that 
people  which  most  fully  secures  the  enjoyment  of  these  blessings  will 
dominate  the  world. 

Medicine  consists  of  the  application  of  scientific  discovery  to  the 
prevention  and  cure  of  disease.  All  else  which  may  go  under  the 
name  of  medicine  is  sham  and  fraud.  Without  advancement  in  the 
physical,  chemical,  and  biologic  sciences,  there  can  be  no  progressive 
movement  in  medicine.  Scientific  knowledge  is  gained  only  by  obser- 
vation and  experiment.  Before  the  time  of  Jenner,  we  are  told  by 
the  historian,  it  was  unusual  to  meet  in  London  one  whose  face  was 
not  marked  by  smallpox.  There  was  a  popular  belief  that  one  who 
had  cowpox  was  immune  to  smallpox.  Jenner  put  this  belief  to  a 
scientific  test.  The  result  was  the  discovery  of  vaccination,  and  this 
secured  the  abolition  of  this  disfigurement  and  a  marked  reduction 
in  mortality.  In  1849,  a  village  doctor,  with  a  crude  microscope, 


10  INTRODUCTION 

studied  the  blood  of  animals  sick  with  anthrax  and  compared  it  with 
that  of  healthy  ones.  He  discovered  the  anthrax  bacillus.  This  work 
was  extended  by  Davaine,  Pasteur,  Koch,  and  others,  and  from  this, 
the  science  of  bacteriology  has  been  developed.  The  particulate  causes 
of  many  infectious  diseases  have  been  recognized,  isolated,  and  their 
effects  on  animals  demonstrated.  Many  of  the  mysteries  of  contagion 
have  been  revealed  and  the  conditions  of  the  transmission  of  disease 
made  known.  The  fundamental  principles  of  preventive  medicine  have 
been  developed  into  a  science  which  is  to-day  the  most  potent  factor 
in  the  progress  of  civilization.  Finlay  suspected  a  certain  mosquito 
to  be  the  carrier  of  the  virus  of  yellow  fever.  Reed  and  his  co-workers 
demonstrated  the  truth  of  this  theory,  the  work  of  Gorgas  has  freed 
Havana  from  the  pestilence,  and  the  construction  of  the  Panama  Canal 
is  an  accomplished  fact. 

Laveran  discovered  Plasmodium  malariae.  Ross  studied  its  life  his- 
tory, and  the  fetters  of  a  disease  that  has  so  long  retarded  the  progress 
of  man,  have  been  broken.  Mitchell  and  Reichert  investigated  the 
poisonous  properties  of  snake  venom.  Sewall  immunized  animals  with 
it.  Ehrlich  studied  the  similar  bodies,  abrin,  ricin  and  diphtheria 
toxin,  and  von  Behring  and  Roux  gave  the  world  antitoxin,  the 
magical  curative  value  of  which  has  greatly  reduced  the  mortality 
from  diphtheria.  The  experiments  of  Villemin  demonstrated  the  con- 
tagious nature  of  tuberculosis,  long  suspected  and  frequently  denied. 
The  diligent  research  of  Koch  resulted  in  the  recognition  and  isolation 
of  the  causative  agent,  and  since  this  discovery  the  mortality  of  the 
Great  White  Plague  in  Europe  and  the  United  States  has  been  dimin- 
ished more  than  half.  It  is,  then,  within  the  range  of  sanity  to  look 
forward  to  the  time  when  the  former  "Captain  of  the  hosts  of  death" 
will  be  known  only  by  the  fearful  records  he  once  made  in  the  history 
of  man's  struggle  to  be  relieved  from  the  heavy  tribute  paid  to 
infection. 

We  boast  of  a  great  civilization,  but  this  is  justified  only  within 
limits.  Science  more  nearly  dominates  the  world  than  at  any  time  in 
the  past.  Learning  permeates  the  masses  more  deeply,  but  credulity 
and  ignorance  are  widely  prevalent.  In  this  country  of  nearly  one 
hundred  millions,  there  are  thousands  whose  greed  impedes  the  prog- 
ress of  the  whole,  tens  of  thousands  whose  ignorance  retards  their 


INTRODUCTION  11 

own  growth,  and  other  thousands  who  live  by  crime  and  procreate 
their  kind  to  feed  on  generations  to  come.  We  have  our  schools, 
colleges,  and  universities,  while  our  almshouses,  insane  asylums,  and 
penal  institutions  are  full.  In  our  cities  we  see  the  palatial  homes 
of  the  very  rich,  the  splendid  temples  of  trade  and  commerce,  the 
slums  of  want  and  poverty,  and  the  homes,  both  rich  and  squalid,  of 
vice  and  crime.  No  nation  in  this  condition  can  be  given  a  clean  bill 
of  health.  Our  hilltops  are  illuminated  by  the  light  of  knowledge,  but 
our  valleys  are  covered  by  the  clouds  of  ignorance.  We  have  not 
emerged  from  the  shadows  of  the  dark  ages.  The  historian  of  the 
future  will  have  no  difficulty  in  convincing  his  readers  that  those  who 
lived  at  the  beginning  of  the  twentieth  century  were  but  slightly 
removed  from  barbarism,  as  he  will  tell  that  the  school,  saloon,  and 
house  of  prostitution  flourished  in  close  proximity;  that  the  capitalist 
worked  his  employees  under  conditions  which  precluded  soundness 
of  body;  that  the  labor  union  man  dynamited  buildings;  that  while 
we  sent  missionaries  to  convert  the  Moslem  and  the  Buddhist,  ten 
thousand  murders  were  committed  annually  in  the  midst  of  us,  and 
that  a  large  percentage  of  our  mortality  was  due  to  preventable  disease. 
Evidently  there  is  much  to  be  done  before  we  pass  out  from  the 
shadows  of  ignorance  into  the  full  light  of  knowledge.  In  this  great 
work  for  the  betterment  of  the  race  the  medical  profession  has  impor- 
tant duties  to  perform.  I  do  not  mean  to  imply  that  the  uplift  of 
mankind  devolves  wholly  on  the  medical  man.  The  burdens  are  too 
many  and  too  diversified,  the  ascent  is  too  steep  and  the  pathways 
are  too  rough  for  one  profession  to  hope  to  reach  unaided  the  high 
plateau  we  seek.  Moreover,  other  callings  have  no  right,  and  should 
have  no  desire  to  shirk  the  moral  responsibilities  which  rest  alike  on 
all.  But  in  past  ages,  medical  men  have  been  the  chief  torch  bearers 
of  science,  whose  light  is  the  only  one  in  which  man  may  safely  walk, 
and  we  must  keep  and  transmit  this  trust  and  honor  to  those  who 
follow  us.  I  know  of  no  scientific  discovery,  from  the  ignition  of 
wood  by  friction  to  the  demonstration  of  the  causes  of  infection  and 
the  restriction  of  disease,  which  has  not  sooner  or  later  assisted  in  the 
betterment  of  the  race.  It  may  be  added  that  nothing  else  has  so  aided 
man  in  his  slow  and  halting  progress  from  the  pestilential  marshes 
of  ignorance  to  the  open  uplands  of  intelligence. 


12  INTRODUCTION 

In  so  great  a  work  as  the  eradication  of  preventable  disease,  all 
intelligent  people  must  cooperate.  The  law  must  support  by  proper 
enactments,  and  these  must  be  enforced  with  justice  and  intelligence; 
it  must  recognize  that  the  right  to  enjoy  health  is  quite  as  sacred  as 
that  to  possess  property;  that  to  poison  men  in  factories  and  mines, 
to  pollute  drinking-water  supplies,  to  adulterate  foods,  and  to  drug 
with  nostrums,  is  manslaughter.  Religion  must  teach  the  sanctity  of 
the  body  as  well  as  that  of  the  soul,  that  ignorance  is  sin  and  knowledge 
virtue,  that  parenthood  is  the  holiest  function  performed  by  man,  and 
that  to  transmit  disease  is  an  unpardonable  sin.  The  teacher  must 
know  hygiene  as  well  as  mathematics.  The  capitalist  must  recognize 
that  improvement  in  health  and  growth  in  intelligence  increase  the 
efficiency  of  labor.  There  never  has  been  a  time  when  scientific  medi- 
cine has  had  so  many  and  such  efficient  and  appreciative  helpers  as 
it  has  to-day.  Our  sanitary  laws  are  for  the  most  part  good,  but 
their  administration  is  weak,  on  account  of  ignorance.  The  pulpits 
of  the  land  are  open,  for  the  most  part,  to  the  sanitarian.  The 
respectable  newspapers  are  most  effective  in  the  crusade  against 
quackery  and  disease.  The  philanthropist  has  learned  that  the  advance- 
ment of  science  confers  the  greatest  and  most  lasting  benefits  on  man. 

There  is  a  moral  obligation  to  be  intelligent.  Ignorance  is  a  vice 
and  when  it  results  in  injury  to  anyone,  it  becomes  a  crime,  a  moral, 
if  not  a  statutory  one.  To  infect  another  with  disease,  either  directly 
or  indirectly,  as  a  result  of  ignorance,  is  an  immoral  act.  The  purpose 
of  government  is  to  protect  its  citizens,  and  a  government  which  fails 
to  shelter  its  citizens  against  infection  is  neither  intelligent  nor  moral. 
To  transmit  disease  of  body  or  mind  to  offspring  is  an  unpardonable 
sin.  In  a  reasonable  sense  it  is  worse  than  murder,  because  it  projects 
suffering  into  the  future  indefinitely. 

That  medicine  has  become  a  fundamental  social  service  must  be 
evident.  To  return  one  incapacitated  by  illness  or  injury  to  the  con- 
dition of  self-support,  benefits  not  only  the  individual,  but  the  com- 
munity, inasmuch  as  it  increases  its  productive  capacity.  Infirmity  is 
a  direct  burden  on  the  individual  and  scarcely  less  direct  on  the  com- 
munity. Weakness  in  any  part  diminishes  the  strength  of  the  whole. 
It  is  a  fully  established  principle  in  social  economy  that  widespread 
intelligence  and  growth  in  knowledge  are  beneficial  to  the'  state.  It 


INTRODUCTION  13 

was  in  full  recognition  of  this  that  the  framers  of  the  ordinance  of 
1787  wrote  into  that  immortal  document:  "Religion,  morality  and 
knowledge  being  necessary  to  good  government  and  the  happiness  of 
mankind,  schools  and  the  means  of  education  shall  forever  be  encour- 
aged." The  territory  of  the  Northwest,  the  government  of  which  was 
created  in  this  ordinance,  was  at  that  time  a  vast  waste  of  forest  and 
prairie,  furnishing  a  scant  and  precarious  subsistence  for  savage  tribes 
and  attracting  to  its  borders  a  few  of  the  most  hardy  sons  of  civiliza- 
tion. The  knowledge,  for  whose  growth  and  diffusion  the  wise  provision 
was  made,  has  drained  the  malarial  marshes,  converted  wild  prairie 
and  tangled  wood  into  fruitful  orchards  and  fertile  fields,  dotted  the 
whole  area  with  neat  villages,  reared  great  cities,  linked  all  parts  with 
steam  and  electric  roads,  and  provided  comfortable  homes  and  abundant 
food  for  millions.  The  men  who  wrote  the  ordinance  of  1787  left  a 
great  inheritance  which  is  temporarily  in  our  possession.  Let  us  write 
into  this  great  document:  "Every  ill  which  can  be  relieved  shall  be 
removed,  and  every  preventable  disease  shall  be  prevented."  The 
wisdom  of  our  fathers  has  secured  for  us  a  greater  measure  of  health 
and  a  longer  term  of  life;  let  us  do  as  well  for  those  who  are  to 
possess  this  fair  land  in  the  next  generation.  Let  us  live  not  only 
for  ourselves  and  the  present,  but  for  the  greater  and  more  intelligent 
life  of  the  future. 

Not  myself,  but  the  truth  that  in  life  I  have  spoken, 
Not  myself,  but  the  seed  that  in  life  I  have  sown 
Shall  pass  into  ages  —  all  about  me  forgotten 
Save  the  truth  I  have  spoken,  the  things  I  have  done. 

All  things  are  relative  and  health  is  no  exception.  With  a  greater 
degree  of  health  among  all,  religion  will  become  more  effective  for 
good,  morality  will  have  a  deeper  significance  and  a  wider  applica- 
tion, and  knowledge  will  multiply  and  distribute  its  blessings  more 
widely. 

After  the  last  epidemic  of  the  plague  in  London,  in  1665,  the  death- 
rate,  so  far  as  it  can  be  ascertained,  fell  to  between  seventy  and  eighty 
per  1,000.  During  the  next  century  it  fell  as  low  as  fifty,  but  fluctu- 
ated greatly  with  recurring  epidemics  of  typhus  and  smallpox.  In  the 
nineteenth,  it  gradually  and  quite  constantly  decreased  and  is  now 
about  fourteeen.  In  1879-80,  the  first  year  in  which  the  mortality 


14 


INTRODUCTION 


statistics  of  the  United  States  possess  sufficient  accuracy  to  be  of  any 
value,  the  death-rate  in  the  registered  area  was  19.8;  in  1912  it  was 
13.9  —  a  decrease  of  30  per  cent.  During  the  same  time  the  mortality 
from  typhoid  fever  has  decreased  50  per  cent. ;  that  from  scarlet  fever 
89  per  cent. ;  that  from  diphtheria  84  per  cent. ;  that  from  tuberculosis 
54  per  cent.  Hoffman  states  that  had  the  death-rate  for  tuberculosis 
in  1901  continued,  there  would  have  been  200,000  more  deaths  from 
this  cause  from  that  date  to"  1911  than  actually  did  occur,  so  that  the 
actual  saving  of  lives  from  death  by  tuberculosis  accomplished  in  that 
decennium  averaged  20,000  a  year.  Preventive  medicine  measures  its 
successes  by  the  number  of  lives  saved,  and  20,000  a  year  preserved 
from  death  from  one  disease  is  no  small  triumph.  In  the  last  century 
the  average  of  human  life  has  been  increased  fifteen  years  and  this 
increase  could  be  duplicated  in  the  next  twenty  years  if  the  facts  we 
now  possess  were  effectively  employed.  Hoffman  further  states  that 
the  addition  to  the  material  wealth  of  this  country  secured  by  the 
reduction  of  deaths  from  tuberculosis  within  ten  years  amounts  approx- 
imately to  6,200,000  years  of  human  life,  covering  its  most  productive 
period.  Medicine  discovered  the  facts  which  have  made  this  great 
work  possible  and  has  directed  their  application.  With  evidence  of 
this  kind  before  them,  will  our  lawmakers  listen  to  those  who  demand 
recognition  as  practitioners  of  medicine  without  proper  qualifications  ? 
The  following  figures  give  the  death-rates  from  all  causes  and 
from  each  of  certain  infectious  diseases  in  the  registered  area  of  the 
United  States  since  the  census  of  the  year  of  1879-80 : 


.L-'CciLllO   pCI 

Year 

1,000  from 

Scarlet  fever 

Typhoid  fever 

Diphtheria 

Tuberculosis 

all  causes 

(all  forms) 

1879-80 

19.8 

54.0 

34.0 

112.6 

326.2 

1889-90 

19.6 

13.6 

46.3 

97.8 

267.4 

1899 

17.8 

11.6 

33.8 

45.2 

205.2 

1900 

17.6 

10.2 

35.9 

43.3 

201.9 

1901 

16.5 

13.1 

32.3 

34.0 

196.9 

1902 

15.9 

12.6 

34.3 

30.8 

184.5 

1903 

16.0 

12.2 

34.1 

31.7 

188.5 

1904 

16.5 

10.8 

31.7 

28.3 

200.7 

1905 

16.0 

6.7 

27.8 

23.6 

192.3 

1906 

15.7 

7.7 

31.3 

25.7 

180.2 

1907 

16.0 

10.0 

29.5 

23.6 

178.5 

1908 

14.8 

11.9 

24.3 

21.5 

167.6 

1909 

14.4 

11.4 

21.1 

20.4 

160.8 

1910 

15.0 

11.6 

23.5 

21.4 

160.3 

1911 

14.2 

8.8 

21.0 

18.9 

158.9 

1912 

13.9 

6.7 

16.5 

18.2 

149.5 

1913 

14.1 

8.7 

17.9 

18.8 

147.6 

INTRODUCTION  15 

Preventive  medicine,  still  in  its  youth,  has  accomplished  great 
things.  As  I  have  stated,  within  the  past  thirty  years  in  this  country 
the  mortality  from  tuberculosis  has  been  reduced  more  than  half,  and 
with  scarlet  fever  and  diphtheria,  the  results  have  been  more  striking. 
Within  the  past  ten  years,  the  average  life  has  been  increased  four 
years.  Great  epidemics  which  once  devasted  continents  are  no  longer 
known  in  the  more  intelligent  parts  of  the  world.  In  fact,  it  may  be 
said  that  the  death-rate  is  now  an  excellent  measure  of  intelligence. 
In  1911  the  death-rate  in  London  was  15  per  thousand,  while  that  of 
Moscow  was  27.3.  Preventive  medicine  is  the  keystone  of  the  trium- 
phal arch  of  modern  civilization  and  its  displacement  would  precipitate 
mankind  into  relative  barbarism.  Should  the  health  administrators  of 
any  great  commercial  center  fail,  for  even  a  few  months,  to  exercise 
the  function  of  restricting  disease,  the  history  of  the  epidemics  of 
the  middle  ages  might  be  repeated.  Great  things  have  been  done, 
but  greater  tasks  lie  before  us,  and  their  accomplishment  depends  on 
the  scientific  wisdom  of  the  medical  profession  and  the  intelligence 
of  the  people.  Without  the  harmonious  adjustment  of  these  forces 
the  greatest  efficiency  cannot  be  secured.  While  the  mortality  from 
tuberculosis  has  been  reduced  half  in  the  past  thirty-five  years,  we 
must  not  assume  that  the  total  eradication  of  this  disease  will  be 
accomplished  in  the  same  number  of  years.  Only  the  more  progressive 
members  of  the  profession  have  taken  the  initiative,  and  only  the  more 
intelligent  members  of  the  community  have  responded.  Intelligence 
and  the  sense  of  moral  responsibility  must  grow  as  the  work  proceeds. 
It  remains  for  all  who  have  the  welfare  of  the  race  at  heart  to  plan 
wisely  and  carry  fonvard  courageously  the  campaign  against  greed, 
ignorance  and  disease. 


PART    I 
INFECTION 


CHAPTER    II 


HISTORICAL  INTRODUCTION 

The  oldest  and  most  persistent  belief  holds  that  disease  is  an 
infliction  imposed  on  man  by  some  supernatural  power.  This  doctrine 
was  handed  down  by  tradition  to  the  earliest  civilizations,  was  incor- 
porated in  their  records  and  is  held  by  many  to-day.  Some  have 
attributed  disease  to  evil  spirits  and  others  have  regarded  it  as  a 
dispensation  of  their  gods.  The  Babylonians  regarded  disease  "as 
the  work  of  demons  which  swarmed  in  the  earth,  air  and  water,  and 
against  which  long  litanies  and  incantations  were  recited."  In  the 
hand  of  the  Jehovah  of  the  Jews  disease  was  a  whip  of  chastisement 
which  fell  at  will  on  the  chosen  people  or  their  enemies.  "I  will  put 
none  of  those  diseases  upon  thee  which  I  have  brought  upon  the 
Egyptians ;  for  I  am  the  Lord  that  healeth  thee."  There  is  no  book 
of  the  middle  ages  down  to  the  eighteenth  century,  describing  an 
epidemic  which  does  not  attribute  it  to  the  wrath  of  God.  Job 
ascribed  his  own  pains  to  the  "arrows  of  the  Almighty."  Luther 
wrote  that  "pestilence,  fever  and  other  severe  diseases  are  naught  else 
than  the  devil's  work."  Cotton  Mather  described  disease  as  "flagellum 
Dei  pro  pecatis  mundi." 

"The  American  Indian  medicine  man  or  the  Asiatic  Samoyed  does 
his  best  to  frighten  away  the  demons  of  disease  by  assuming  a  terrify- 
ing aspect,  covering  himself  with  the  skins  of  animals  so  as  to  resemble 
an  enormous  beast  walking  on  his  hind  legs,  resorting  to  such  demon- 
strations as  shouting,  raving,  slapping  his  hands  or  shaking  a  rattle, 
and  pretending  (or  endeavoring)  to  extract  the  active  principle  of  the 
disease  by  sucking  it  through  a  hollow  tube.  .  .  .  We  may  smile 
at  these  phases  of  Shamanistic  procedure,  but,  except  for  the  noise, 
they  are  not  essentially  different  from  the  mind-medicine  or  faith- 
healing  of  our  own  day.  Both  rely  upon  psychotherapy  and  sug- 
gestion, and  for  a  sick  savage,  the  fantastic  clamor  made  about  him 
might  be  conceivably  as  effective  as  the  quieter  methods  of  Christian 
Science,  to  a  modern  nervous  patient."  (Garrison.) 


20  HISTORICAL    REVIEW 

A  doctrine  quite  as  old,  but  with  a  smaller  following  at  present, 
taught  that  all  the  joys  and  ills  of  man  are  determined  by  the  position 
of  the  heavenly  bodies.  Even  within  the  present  generation  there  are 
those  who  believe  that  famine,  war  and  pestilence  are  determined  by 
the  spots  on  the  sun  or  by  the  juxtaposition  of  certain  planets.  Our 
great  lexicographer,  Noah  Webster,  wrote  a  book  to  prove  that  epi- 
demics are  due  to  earthquakes  and  other  terrestrial  disturbances. 

Hippocrates  taught  that  epidemics  are  due  to  a  pestilential  condi- 
tion of  the  air.  This  theory  dominated  the  medical  profession  for 
more  than  two  thousand  years,  and  still  colors  some  of  our  conceptions 
of  infection.  Quite  naturally,  such  a  theory  is  liable  to  many  modifi- 
cations. How  does  the  air  become  pestilential?  This  question  has 
been  answered  in  numberless  ways.  Some  say  it  is  made  so  by  evil 
spirits;  by  an  angered  God;  by  the  influence  of  heavenly  bodies;  by 
terrestrial  disturbances ;  by  prevailing  winds ;  by  emanations  from  earth 
or  water;  etc.  It  is  natural  for  man  to  believe  in  the  evil  genius  of 
the  locality  in  which  ills  befall  him.  In  1898,  intelligent  army  officers 
told  with  bated  breath  that  the  word  "Chickamauga"  means  river  of 
death.  They  believed  that  the  epidemic  of  typhoid  there  prevalent 
was  due  in  part,  at  least,  to  the  miasm  of  the  locality  and  the  disease 
was  called  "Chickamauga  fever."  The  word  malaria  (mal  aria)  owes 
its  origin  to  this  theory.  In  war,  unburied  bodies  of  men  and  animals 
were  supposed  to  fill  the  air  with  deadly  decomposition  products.  It 
was  fear  of  this  that  secured  burial  of  the  numerous  victims  of  the 
plague  in  the  great  epidemics  of  the  middle  ages.  This  fear  had,  in 
part  at  least,  a  religious  basis,  and  burial  was  regarded  not  only  as 
a  necessary  sanitary  measure,  but  as  a  compliance  with  a  divine  com- 
mand. The  unburied  dead  became  a  reproach  to  the  living ;  from  the 
decomposing  body  noxious  and  fatal  emanations  polluted  the  surround- 
ing air,  and  with  this  threatening  weapon,  the  dead  demanded  the 
honor  of  Christian  burial. 

Lowlands  and  swamps  were  supposed  to  be  places  in  which  noxious 
vapors  were  generated  and  from  which  they  spread,  poisoning  the  air 
of  the  surrounding  country.  These  localities  were  shunned,  especially 
after  sunset,  and  the  fear  of  breathing  night  air  became  well  nigh 
universal.  We  now  know  that  the  real  truth  in  this  belief  was  made 


HISTORICAL    REVIEW  21 

plain  by  the  discovery  of  the  transmission  of  malaria  by  mosquitos. 
The  latest  scientific  support  of  the  theory  of  miasm  appeared  in  the 
teachings  of  the  great  sanitarian  of  Munich,  Pettenkoffer.  When  he 
began  his  work  in  the  Bavarian  capital,  about  the  middle  of  the  nine- 
teenth century,  that  city  was  known  as  a  hotbed  of  typhoid  fever. 
Fecal  matter  was  deposited  in  shallow  vaults  and  the  drinking-water 
was  taken  from  shallow  wells.  The  whole  city  was  honeycombed  with 
these  privies  and  wells,  and  the  people  were  drinking  strong  infusions 
of  their  own  excrement.  Pettenkoffer  taught  that  the  fecal  matter 
undergoes  a  ripening  process  in  the  soil  and  thereby  becomes  the  cause 
of  typhoid  fever.  Responding  to  his  teachings,  the  people  of  Munich 
introduced  a  complete  sewerage  system  and  brought  a  pure  drinking- 
water  from  a  distant  mountain  lake.  This  resulted  in  the  eradication 
of  typhoid  fever  and  Pettenkoffer 's  theory  was  justified  by  the  result. 
We  now  know  that  the  typhoid  bacillus  needs  no  ripening  process 
during  the  interval  which  elapses  from  its  passage  from  the  bowels 
of  one  to  its  entrance  into  the  alimentary  canal  of  another.  Petten- 
koffer's  theory  did  not  assume  that  the  noxious  agent  in  the  fecal 
matter  is  a  living  organism,  but  rather  held  that  the  ripening  process 
consists  of  chemical  changes.  From  this,  there  grew  up  the  idea  of 
the  de  novo  origin  of  typhoid  fever.  The  fecal  matter  of  uninfected 
individuals  was  supposed  to  undergo  ripening  processes  in  the  soil 
and  the  products  of  these  changes,  finding  their  way  into  either  water 
or  air,  distributed  the  disease.  This  theory  was  not  only  plausible, 
but  was  in  accord  with  the  then  known  facts.  It  found  ready  support, 
especially  among  army  medical  officers.  However  healthy  men 
appeared  to  be  when  they  went  into  camp,  even  in  locations  which 
could  not  have  been  contaminated  previously,  after  a  few  weeks, 
typhoid  fever  appeared  and  spread  in  proportion  to  the  filthiness  of 
the  camp  and  the  inefficiency  of  the  methods  of  fecal  disposal.  Men 
of  the  highest  intelligence  and  widest  experience  became  firm  sup- 
porters of  the  de  novo  origin  of  typhoid  fever  which  they  regarded 
as  a  filth  disease.  They  believed  that  the  disease  was  spread  by  gases 
generated  in  any  kind  of  filth,  but  more  especially  by  those  developed 
in  fecal  matter. 

The  theory  of  miasm  was  applied  not  only  to  typhoid  fever  and 
malaria,  but  to  all  diseases,  especially  those  appearing  in  epidemic 


22  THEORY    OF    MIASM 

form.  With  sound  sense,  the  Greek  Father  of  Medicine  said  that 
when  a  large  number  of  people  fall  ill  simultaneously  the  cause  must 
be  sought  in  that  which  is  common  to  all,  and  what  can  that  be  save 
the  air  they  breathe  ?  It  was  observed,  however,  that  while  the  whole 
community  was  breathing  the  same  air,  many  remained  well ;  some  had 
eruptive  diseases;  others  diarrheal  disturbances;  and  still  others,  res- 
piratory affections.  This  necessitated  the  division  of  men  into  groups 
according  to  temperament.  With  the  same  factor  in  the  air  the  result 
would  vary  with  the  temperament  of  the  individual. 

The  study  of  the  cholera  epidemics  of  the  nineteenth  century 
removed  the  last  scientific  support  of  the  theory  of  miasm.  It  had 
long  been  a  matter  of  observation  and  record  that  epidemics  travel 
from  east  to  west.  This  was  noted  before  the  Christian  era.  It  was 
frequently  observed  in  classical  times,  and  the  cholera  pandemics  gave 
opportunity  for  collecting  exact  data  on  this  matter.  It  was  found 
that  cholera,  which  is  endemic  about  the  delta  of  the  Ganges,  becomes 
pandemic  on  the  occasion  of  certain  religious  pilgrimages.  The  faithful 
followers  of  Mohammed  from  all  points  of  the  compass  gather  at 
Mecca.  Some  come  from  the  home  of  cholera,  bringing  the  infection 
in  their  bodies.  From  their  discharges  others  become  infected,  and 
as  the  great  concourse  disperses,  bands  of  returning  pilgrims  carry  the 
infection  with  them,  and  the  disease  widens  its  area.  It  travels  just 
as  fast  and  no  faster  than  man  travels.  It  goes  where  he  carries  it 
and  nowhere  else.  When  an  individual  drops  the  infection,  some  one 
else  must  pick  it  up  and  carry  it  on  or  it  ceases  to  spread.  The  gen- 
eral direction  of  the  spread  of  infection  has  always  been  from  east  to 
west  because  the  great  lines  of  human  travel  have  led  from  this  point 
of  the  compass,  but  it  was  found  in  the  study  of  the  cholera  epidemics 
that  whenever  and  wherever  the  paths  of  travel  deviated  from  the 
general  direction,  the  infection  showed  the  same  deviation.  In  other 
words,  it  became  evident  that  infected  man  carried  the  infection  in 
his  own  body.  However,  when  the  pandemics  spread  over  Europe  it 
was  noticed  that,  while  no  place  became  infected  unless  visited  by 
some  infected  individual,  the  disease  established  itself  in  certain  locali- 
ties and  failed  to  do  so  in  other  places.  This  observation  gave  some 
support  to  the  theory  of  miasm.  In  some  soils  the  seeds  of  the  disease 
grew  and  multiplied  while  in  others  they  did  not.  When  the  water- 


GERM    THEORY  23 

supply  of  a  locality  became  infected,  the  disease  spread  among  its 
consumers.  Budd  of  London  was  probably  the  first  to  detect  the  role 
of  infected  water  in  the  dissemination  of  Asiatic  cholera.  Finally  the 
discovery  of  the  specific  bacteria  of  cholera  and  other  diseases  removed 
the  last  support  of  the  theory  of  disease  originating  in  miasmatic 
conditions  of  the  atmosphere. 

The  "germ  theory"  of  disease  found  lodgment  in  the  brain  of  an 
occasional  genius  many  centuries  ago.  Just  who  first  suggested  it 
and  when  are  not  easily  determined,  but  the  argument  ran  something 
as  follows:  Alexandria  was  free  from  the  plague.  A  ship  from  a 
port  where  it  prevailed  came  with  sick  on  board.  Those  associated 
with  the  new  arrivals  acquired  the  disease  and  it  spread  in  an  ever 
widening  circle  until  it  prevailed  throughout  the  city  and  extended  in 
a  similar  manner  to  other  countries.  The  disease  must  be  due  to  a  poison 
of  some  kind.  It  cannot  be  a  chemical  poison,  like  arsenic,  but  it  must 
be  a  living  thing  which  finds  its  way  from  the  body  of  the  sick  to  those 
of  the  well  where  it  grows  and  multiplies  and  in  so  doing  causes  the 
symptoms  of  the  disease  and  death.  Thus,  man's  reason,  stimulated 
by  exact  observation,  caused  him  to  conclude  that  an  epidemic  must 
be  due  to  a  contagium  vivum.  He  might  theorize  concerning  this 
living  thing,  but  he  could  not  demonstrate  its  existence.  It  was  too 
small  for  him  to  see.  In  the  first  century  of  the  Christian  era  Varro 
wrote  that  there  are  swamps  in  which  grow  animals  so  small  that  they 
cannot  be  seen.  They  enter  the  body  through  the  mouth  and  nose 
and  cause  disease.  Others  wrote  to  the  same  effect.  Probably  the 
first  to  see  bacteria  was  the  Dutch  scientist  and  lens  maker,  Leeuwen- 
hoek,  who  near  the  end  of  the  seventeenth  century  described  the 
"animalculae"  which  he  found  under  his  microscope  in  the  examination 
of  tartar  from  the  teeth  and  diarrheal  stools.  In  1849  a  village  doctor 
on  the  Rhine,  with  a  crude  compound  microscope,  saw  rod-like  bodies 
in  the  blood  of  animals  sick  with  anthrax  and  failed  to  find  them  in 
the  blood  of  healthy  animals.  The  science  of  bacteriology  may  be 
said  to  owe  its  birth  to  these  observations.  Independently,  this  work 
was  continued  by  Brauel,  Davaine  and  others,  but  the  founder  of 
exact  and  systematic  knowledge  concerning  the  causal  agents  of  dis- 
ease was  the  great  Frenchman,  Louis  Pasteur. 


24  PASTEUR'S    WORK 

Space  permits  only  a  brief  and  incomplete  statement  of  the  work 
of  Pasteur,  and  in  doing  this  the  chronological  order  will  not  be  fol- 
lowed. He  overthrew  the  doctrine  of  spontaneous  generation. 
Although  Harvey,  two  centuries  earlier,  had  laid  down  the  dictum, 
omne  vivum  ex  vivo,  there  were  those  who  held  that  this  does  not 
hold  for  the  lowest  forms  of  life.  As  Abel  says,  "Homer  wrote  of 
autochthonus  men  who  sprang  from  the  soil;  the  sixteenth  century 
saw  recipes  for  the  manufacture  of  mice  and  frogs,  and  in  later  days, 
it  was  claimed  that  lower  forms  of  animal  life  must  have  developed 
spontaneously  because  the  Bible  makes  no  mention  of  their  having 
been  taken  into  the  ark  by  Noah."  It  was  essential  to  the  development 
of  bacteriology,  which  depends  so  largely  on  sterilization,  to  dispose 
of  spontaneous  generation  and  to  show  that  lower,  as  well  as  higher, 
forms  of  life  breed  true.  This  Pasteur  did  with  the  aid  of  Tyndall, 
and  others.  He  showed  that  fermentation  is  due  to  the  growth  of 
living  organisms,  and  that  each  kind  of  fermentation,  like  that  in 
beer,  wine  and  milk,  is  due  to  specific  organisms.  Furthermore  he 
showed  that  a  temperature  high  enough  to  kill  these  organisms  arrests 
fermentation.  By  this  process,  now  known  as  pasteurization,  he  pre- 
served beer,  wine  and  milk.  Among  this  line  he  went  further  still 
and  demonstrated  that  putrefaction,  like  fermentation,  is  due  to  bac- 
terial growth.  Lister  utilized  this  discovery  in  the  development  of 
antiseptic  surgery  from  which  aseptic  surgery  has  come.  If  each 
kind  of  fermentation  has  its  specific  organism,  why  may  not  each  dis- 
ease have  its  specific  bacterial  cause?  Exposure  to  smallpox  does  not 
develop  typhoid  fever.  The  answer  to  this  question  has  been  given  by 
the  discovery  of  the  specific  causal  agents  of  many  diseases,  and 
when  found  and  tested,  their  specificity  is  demonstrated.  The  anthrax 
bacillus  grown  through  a  hundred  generations  and  then  inoculated 
into  susceptible  animals  induces  anthrax  still.  Pasteur  found  that 
certain  specific  bacteria  can  be  so  attenuated  by  unfavorable  condi- 
tions of  growth  that  they  will  not  develop  the  disease  in  susceptible 
animals,  but  do  impart  to  them  immunity  to  infection  with  virulent 
strains.  In  this  way  he  prepared  vaccines  for  chicken  cholera,  swine 
eryripelas  and  anthrax.  He  also  developed  the  successful  treatment  of 
hydrophobia,  now  used  in  every  part  of  the  world. 


HISTORICAL    REVIEW  25 

The  great  German  scientist,  Koch,  extended  and  developed  the 
work  of  Pasteur.  His  solid  media  and  bacterial  stains  made  the 
growth,  indentification  and  separation  of  bacteria  comparatively  easy. 
His  untiring  labor  led  to  the  discovery  of  the  specific  bacteria  of 
Asiatic  cholera  and  tuberculosis,  and  has  placed  in  man's  hands  the 
possibility  of  completely  eradicating  these  and  other  infectious  diseases. 

The  work  so  firmly  established  by  Pasteur  and  Koch  has  been 
amplified  by  many  workers  in  many  lands  and  has  led  already  to 
marked  reduction  in  both  morbidity  and  mortality  from  the  infectious 
diseases.  Much  has  been  accomplished  in  the  attempt  to  lift  the 
burden  of  unnecessary  disease  from  man,  but  greater  tasks  lie 
before  us. 

This  article  will  be  limited  to  the  bacterial  diseases  and  only  the 
more  common  of  these  can  be  included. 


CHAPTER    III 


BACTERIA 

Morphology.  —  Bacteria  are  microscopic,  unicellular  organisms 
which  appear  in  three  fundamental  forms.  The  spherical  forms  are 
known  as  cocci  and  may  be  single,  in  chains  or  in  bunches.  The  indi- 
viduals may  be  perfectly  spherical,  elliptical  or  lancet-shaped.  The 
individual  pus  coccus  has  a  diameter  of  from  0.4  to  1  micron.*  The 
cylindrical  forms  are  known  as  bacilli.  Some  have  plane  and  others 
convex  or  rounded  ends.  Bacilli  differ  greatly  in  length,  the  longest 
pathogenic  bacillus,  that  of  malignant  edema,  being  9  microns,  and 
the  shortest,  that  of  influenza,  being  0.5  of  a  micron.  Growth  is  in 
the  direction  of  the  long  axis  and  multiplication  by  transverse  fission. 
The  shape  of  the  spirilla  is  sufficiently  indicated  by  the  name.  Involu- 
tion forms  will  not  be  discussed. 

Spore  Formation. — The  only  spore-forming  pathogenic  bacteria 
are  those  of  anthrax,  symptomatic  anthrax,  tetanus  and  malignant 
edema.  The  spores  are  of  endogenous  origin,  are  highly  refractive  to 
light,  and  resistant  to  heat,  and  chemical  disinfectants.  No  bacillus  is 
known  to  form  more  than  two  spores  and  this  is  practically  confined 
to  saprophytic  organisms.  The  appearance  of  two  spores  in  an  anthrax 
bacillus  is  rarely  seen.  The  purpose  of  spore  formation  is  not  mul- 
tiplication but  preservation;  it  is  a  resting  stage.  Spore  formation  is 
a  result  of  the  concentration  of  the  nuclear  substance.  The  spore  may 
be  formed  in  any  part  of  the  cell,  but  the  location  in  the  same  species 
is  usually  constant.  In  some  bacteria  the  spore  does  not  exceed  the 
diameter  of  the  cell;  in  others  it  is  larger.  A  large  spore  located  at 
one  end  of  a  bacillus  gives  it  a  "drum-stick"  appearance ;  when  in  the 
middle,  it  forms  a  "spindle-shaped"  organism.  Untoward  conditions, 
such  as  scarcity  of  food,  the  presence  of  deleterious  agents  and  an 
accumulation  of  metabolic  products,  favor  the  development  of  spores. 


*  A  micron  is  one  thousandth  of  a  millimeter  and  is  the  equivalent  of  1/25,400 
of  an  inch. 


28  BACTERIA 

The  bacterium  passes  into  the  resting  state  and  awaits  more  favorable 
conditions.  When  these  arrive,  whether  it  be  days  or  years  later,  the 
spore  passes  into  the  vegetative  form  and  reproduction  and  multipli- 
cation begin  anew. 

Multiplication. — When  bacteria  reach  a  certain  size,  which  is  fairly 
constant  in  the  species,  the  cells  divide.  In  bacilli  and  vibrios  fission 
occurs  at  right  angles  to  the  long  axis.  In  cocci  the  cleavage  may 
occur  in  only  one  plane  forming  streptococci;  in  two  planes  forming 
staphylococci ;  or  in  three  planes,  forming  sarcinae.  The  rapidity  of 
multiplication  and  growth  to  maturity  varies  with  conditions.  It  has 
been  estimated  that  if  fission  occurs  hourly  without  interruption,  in 
forty-eight  hours  the  descendants  of  a  single  individual  would  number 
more  than  200,000,000.  However,  such  a  rate  of  multiplication  can 
hardly  occur  since  growth  would  be  checked  by  scarcity  of  food  or 
by  the  accumulation  of  excreta  from  the  bacteria  themselves.  The 
rate  of  multiplication  under  most  favorable  conditions  is  the  best 
measure  of  the  intensity  of  life  processes,  and  in  the  case  of  pathogenic 
bacteria,  of  virulence.  The  "generation  period"  is  the  time  interval 
between  fissions  in  the  same  bacillus.  This  varies  greatly  with  varying 
conditions.  Some  of  these  conditions  seem  inherent  in  the  strain  while 
others  are  more  variable.  Under  most  favorable  conditions  the 
cholera  bacillus  has  been  found  to  divide  about  every  half  hour.  When 
a  culture  tube  is  inoculated  there  is  a  variable  period  during  which 
there  is  no  multiplication,  then  fission  begins.  As  the  culture  grows 
older  the  rate  of  multiplication  falls  on  account  of  the  accumulation 
of  metabolic  products.  In  infection  the  rate  of  multiplication  is 
determined  by  the  number  of  bacteria  introduced  as  well  as  by  other 
conditions.  However,  one  strain  of  the  same  species  may  multiply 
a  thousand  times  as  fast  as  another. 

Antagonism. — As  happens  in  all  forms  of  life,  the  most  destructive 
agents  to  bacteria  are  other  bacteria.  It  is  fortunate  that  this  is  true, 
and  man  and  other  animals  profit  greatly  by  the  conflict  continually 
being  waged  between  different  species  of  bacteria.  A  drinking-water 
supply  becomes  contaminated  with  the  typhoid  bacillus  which  flourishes 
for  a  few  days  and  is  then  completely  destroyed  by  other  bacteria. 
So  true  is  this  that  by  the  time  the  disease  has  developed  among 


BACTERIA  29 

those  who  drink  the  water,  there  are  no  longer  typhoid  bacilli  in  the 
water.  The  bacteriologic  examination  of  drinking-water  after  an 
epidemic  has  developed,  is  in  the  large  majority  of  instances,  a  useless 
procedure.  A  city's  water-supply  should  be  examined  daily  in  order 
to  be  of  value.  The  weapons  used  in  this  warfare  among  bacteria 
are  many  and  varied.  Some  simply  eat  up  the  food  supply  and  the 
invaders  die  of  starvation.  Others  produce  waste  products  which  are 
harmful  to  other  species.  Anthrax  bacilli  planted  in  sterile  cholera 
cultures  are  greatly  weakened.  Sterile  cultures  of  the  pyocyaneus 
dissolve  anthrax  bacilli.  Some  change  the  reaction  of  the  common 
medium  by  the  development  of  acid  or  alkali  and  their  enemies  die. 
The  streptococcus  kills  the  plague  bacillus,  and  thus  the  conflict  of 
nations  and  races  goes  on  among  the  unicellular  organisms  much  as 
it  does  among  the  lords  of  creation. 

Symbiosis. — Some  species  form  allied  armies  and  contend  against 
a  common  enemy  or  overrun  a  foreign  country.  The  pus  bacteria  are 
found  in  many  combinations  and  most  men  die  from  diseases  in 
which  these  cocci  play  an  important  part.  After  the  tubercle  bacillus 
has  fed  on  one's  lungs  for  years  and  prepared  the  soil,  some  pus 
germ  finds  its  way  in  before  death  and  contributes  largely  to  its  com- 
ing. The  cancer  cell  opens  up  ports  of  entry  through  which  pus 
organisms  enter.  The  lesions  of  syphilis  are  plundered  and  looted  by 
the  hordes  of  cocci.  Thus,  as  Mayo  has  pointed  out,  sepsis  plays  an 
important  role  in  the  last  acts  of  the  three  great  tragedies  of  life; 
tuberculosis,  cancer  and  syphilis.  Some  pathogenic  bacteria  receive 
aid  from  organisms  which  by  themselves  are  harmless.  The  tetanus 
bacillus  is  much  more  virulent  when  it  enters  the  animal  body  in 
company  with  certain  saprophytes.  When  alone,  the  phagocytes 
speedily  fall  on  and  devour  it,  while  certain  products  of  the  growth 
of  its  friend  repel  the  phagocytes. 

Capsules. — Some  bacteria  are  surrounded  by  mucilaginous  capsules. 
When  two  or  more  individuals  are  attached,  the  capsule  usually 
includes  the  group,  and  when  many  are  imbedded  in  one  large  capsule 
the  whole  is  known  as  a  zooglia.  The  capsule  is  believed  to  be  formed 
for  protective  purposes,  since  many  bacteria  develop  them  only  when 
in  the  animal  or  when  grown  in  animal  fluids,  secretions  or  excre- 


30  BACTERIA 

tions.  The  presence  of  deleterious  agents,  such  as  arsenic,  seems  to 
favor  the  development  of  capsules. 

Flagella. — All  bacteria  show  passive  movements  when  suspended 
in  fluids  and  watched  under  the  microscope.  Such  motion  is  known 
as  molecular  or  Brownian  and  is  common  to  all  finely  divided  par- 
ticles when  suspended  in  fluid.  Apart  from  this,  certain  bacteria  are 
capable  of  active  motion,  which  is  accomplished  by  the  contractions 
of  flagella  or  whips.  Those  without  flagella  have  no  active  motion. 
There  may  be  only  one  whip  at  one  end,  as  in  the  cholera  bacillus; 
a  single  whip  at  each  end,  as  in  many  saprophytic  vibrios;  a  bunch  of 
whips  at  one  end  as  in  certain  large  saprophytic  vibrios ;  and  many 
whips  distributed  over  the  cell,  as  in  the  typhoid  bacillus.  The  flagella 
seem  to  be  outgrowths  from  the  ectoplasm  and  they  may  be  removed 
from  certain  bacteria  by  shaking  and  then  centrifuging,  or  by  filtra- 
tion through  porcelain.  Their  presence  favors  agglutination,  which 
however,  is  not  wholly  dependent  on  them. 

Oxygen  Need. — Pasteur  observed  that  some  bacteria  grow  best 
when  supplied  with  oxygen,  while  others  have  their  optimum  growth 
when  this  element  is  excluded.  The  former  he  designated  as  aerobic 
and  the  latter  as  anaerobic.  Further  study  has  divided  bacteria  accord- 
ing to  their  need  of  oxygen  into  the  following  classes : 

1.  Obligate  aerobes  are  those  which  will  not  grow  save  in  the 
presence  of  free  oxygen.     This  does  not  mean  that  they  must  have 
an   abundant  air-supply,  because  some   do  grow  when  the  oxygen 
tension  is  only  one-hundredth  that  of  the  air.    Among  the  pathogenic 
bacteria,  the  plague  and  influenza  bacilli  and  the  pneumococcus  and 
gonococcus  belong  to  this  group.     An  excess  of  oxygen  may  prove 
harmful  to  even  the  obligate  aerobes. 

2.  Facultative  anaerobic  bacteria  are  those  that  grow  best  in  the 
presence   of   oxygen,   but  may  grow   when   this   element   is   wholly 
excluded.     Many  pathogenic  organisms  belong  to  this  class,  such  as 
the  cholera  vibrio,  anthrax  and  typhoid  bacillus  and  pus  cocci. 

3.  Obligate  anaerobes  are  bacteria  which  grow  only  in  the  absence 
of  free  oxygen.    In  this  group  are  the  bacilli  of  tetanus,  symptomatic 
anthrax  and  malignant  edema.     These  bacteria  obtain  their  oxygen 
if  they  utilize  this  element  at  all,  from  the  combined  oxygen  in  their 


BACTERIA  31 

pabulum.  Pasteur  found  that  fermentation  is  due  to  obligate  anaerobes 
and  he  defined  fermentation  as  life  without  oxygen.  However,  this 
does  not  mean  that  all  life  without  oxygen  results  in  fermentation. 
The  growth  of  bacteria  of  this  group  is  favored  by  the  presence  of 
reducing  agents  in  the  medium.  Anaerobic  bacteria  may  grow  in  the 
presence  of  free  oxygen  provided  there  are  present  aerobic  organisms 
which  absorb  all  the  oxygen.  The  development  of  tetanus  is  favored 
by  puncture  wounds,  also  by  the  presence  of  aerobic  bacteria. 

Structure. — In  the  higher  plants  and  animals,  all  cells  capable  of 
multiplication  consist  of  protoplasm  and  nucleus.  There  has  been 
much  controversy  among  bacteriologists  concerning  the  structure  of 
the  bacterial  cell.  Some  say  that  this  cell  has  no  nucleus  because,  with 
the  analine  dyes,  it  stains  uniformly.  Others  say  it  is  all  nucleus 
because  the  staining  which  it  takes  throughout  is  nuclear.  These  are 
the  two  extremes,  but  most  agree  that  the  greater  part  of  the  bacterial 
cell  consists  of  nuclear  material.  Fats  and  waxes  have  been  accumu- 
lated especially  by  those  organisms,  as  the  tubercle  bacillus,  which 
have  lived  so  long  as  parasites.  Food  material,  inorganic  salts,  fer- 
ments and  various  extractives  are  present  in  the  bacterial  cell,  but 
for  the  most  part  it  is  of  nuclear  composition.  Its  chief  function  is  to 
multiply,  and  this  is  accomplished  in  the  simplest  possible  way  by 
nuclear  division.  Most  authorities  define  bacteria  as  low  forms  of 
plant  life.  The  one  characteristic  and  constant  constituent  of  the  plant 
cell  is  cellulose.  This  certainly  does  not  exist  in  the  pathogenic  bacilli 
and  bacteria  are  not  plants.  This  seems  certain  unless  we  radically 
change  our  conception  of  the  plant  cell.  Bacteria  may  be  more 
properly  defined  as  nuclei,  probably  protected  by  a  protein  ectoplasm. 
I  and  my  students  have  devoted  many  years  of  work  to  this  subject 
and  we  have  shown  that  chemically  the  greater  part  of  the  bacterial 
cell  is  nuclear  substance.  It  contains  two  carbohydrates,  one  of  which 
has  been  located  in  the  nucleic  acid  group  while  the  position  of  the 
other  has  not  been  determined.  It  yields  phosphorus  and  xanthin 
bases  and  when  broken  up  with  acids  or  alkalies  supplies  mono-amino 
and  diamino  acids.  Chemically,  bacteria  are  nucleoproteins.  It  has 
been  assumed  by  some  that,  chemically,  bacteria  are  of  simple  struc- 
ure.  This  is  pure  assumption  and  rests  solely  on  the  fact  that, 


32  BACTERIA 

morphologically,  bacteria  are  relatively  simple.  Biologically  and 
chemically  their  structure  is  as  complicated  as  that  of  the  highest  cells 
of  the  animal  body.  In  common  with  all  proteins,  bacterial  cellular 
substance  contains  a  powerful  poison.  This  is  true  alike  of  pathogenic 
and  non-pathogenic  bacteria  and  true  of  all  proteins — bacterial,  vege- 
table and  animal. 

In  fact,  bacteria  in  their  essential  parts  are  living  molecules,  of 
definite  chemical  composition  and  structure.  In  different  species  the 
molecular  composition  differs.  As  Benecke  has  shown,  the  pyocyaneus 
requires  for  its  growth,  in  addition  to  protein  substances,  two  ele- 
ments, potassium  and  magnesium.  The  former  cannot  be  replaced  by 
sodium  or  ammonium,  nor  the  latter  by  calcium.  The  tubercle  bacillus 
needs  glycerin  in  order  to  assimilate  amino-acids,  carbohydrates  and 
organic  acids.  Cramer  found  that  the  cholera  bacillus  assimilates  as 
much  as  95  per  cent,  of  the  nitrogen  in  alkaline  bouillon,  and  at  most 
3  per  cent,  of  that  in  Uschinsky's  solution.  The  obligate  parasites 
feed  only  on  the  fluids  and  tissues  of  the  animal  body  and  some  only 
on  some  particular  species  of  animal.  The  influenza  bacillus  grows 
only  on  media  containing  hemoglobin  or  some  chemically  related 
body. 

Metabolism. — Every  living  thing  must  feed,  assimilate  and  elim- 
inate. It  thrives  and  multiplies  when  food  is  abundant  and  conditions 
of  life  are  favorable.  It  hungers  and  dies  when  the  food  supply  fails. 
These  things  are  as  true  of  unicellular  as  of  multicellular  forms  of 
life.  All  bacteria,  even  the  anaerobic,  absorb  oxygen  and  eliminate 
carbonic  acid.  In  this  gaseous  exchange  more  oxygen  is  absorbed  than 
is  eliminated  in  the  form  of  carbonic  acid.  This  shows  that  some 
oxygen  is  used  in  nitrogen  metabolism.  When  the  food  supply  is 
suddenly  withdrawn  in  the  midst  of  rapid  multiplication,  the  death- 
rate  is  great,  and  greater  among  the  young  than  among  the  older 
individuals.  Fisher  has  shown  that  when  a  growth  of  cholera  bacilli 
twenty-four  hours  old  is  suddenly  transferred  to  salt  solution,  all  the 
organisms  die  within  thirty-six  hours.  With  older  cultures  some  live 
bacilli  are  found  much  later  and  with  a  seven-day  culture,  some  will 
be  found  to  be  alive  after  fifty  days.  When  the  food  supply  is  gradu- 
ally withdrawn  the  death-rate  is  not  so  high  and  the  more  hardy 


BACTERIA  33 

individuals  retain  their  vitality  for  months  and  even  years,  especially 
at  low  temperature.  The  respiratory  quotient  remains  constant  in 
the  same  species  under  identical  conditions  and  is  a  measure  of  rate 
of  growth  and  multiplication. 

All  living  cells  must  depend  on  the  pabulum  within  their  reach. 
This  must  be  digested  or  broken  up  into  particles  which  will  fit  into 
the  bacterial  molecule.  This  is  accomplished  by  agents  which  we 
designate  as  ferments  or  enzymes.  Each  species  of  bacteria  elaborates 
its  own  specific  enzymes,  the  functions  of  which  are  to  cut  the 
pabulum  into  proper  blocks  and  to  place  these  blocks  in  the  structure 
of  the  cell.  These  enzymes  are  specific  in  two  senses.  First,  they  are 
specific  in  origin;  the  ferments  produced  by  typhoid  bacilli  are  not 
identical  with  those  of  anthrax  bacilli.  Secondly,  they  are  specific 
in  their  action.  Given  the  same  pabulum,  the  shape  and  size  of  the 
blocks  into  which  it  is  split  differ  with  the  ferment  acting  on  it. 
Besides,  a  given  ferment  cannot  act  on  all  pabulum.  What  is  food  to 
one  bacterium  may  be  of  no  value  to  another. 

Pathogenitity. — Why  is  it  that  one  bacterium  is  capable  of  induc- 
ing disease  while  another  is  harmless?  The  answer  to  this  is  quite 
clear.  Some  bacteria  can  feed  only  on  dead  matter.  Their  ferments 
will  not  prepare  the  fluid  and  tissues  of  the  animal  body  for  the 
sustenance  of  their  cells;  or  it  may  be  that  the  ferments  of  the  body 
cells  digest  these  bacteria  and  prevent  their  growth.  These  bacteria, 
which  compose  the  great  majority  of  existing  species  are  known  as 
saprophytes.  There  are  other  bacteria  which  can  digest,  absorb  and 
eliminate  the  constituents  of  the  fluids  and  tissues  of  the  animal  body 
and  which  are  not  digested  by  the  body  cells.  These  are  parasites  and 
their  growth  and  reproduction  in  the  body  cause  disease  and  conse- 
quently such  bacteria  are  said  to  be  pathogenic.  Such  an  organism 
may  be  able  to  grow  in  one  species  of  animal  and  not  in  others.  It 
is  pathogenic  only  to  those  animals  in  which  it  can  grow.  It  may  be 
able  to  grow  in  certain  individuals  of  a  species  and  not  in  others.  To 
the  man  who  has  had  smallpox  or  has  been  properly  vaccinated,  the 
smallpox  virus  is  not  pathogenic.  Vaccination  has  developed  in  the 
body  cells  the  function  of  producing  a  ferment  which  digests  small- 
pox virus  and  consequently  this  cannot  grow  and  multiply  in  the  body 
of  the  vaccinated  man. 


CHAPTER    IV 


AVENUES    OF    INFECTION 

The  Skin.  —  While  certain  parasites,  molds  and  fungi  may  be 
implanted  on  a  healthy  skin  by  contact,  either  direct  or  indirect,  there 
is  no  known  bacterium  which  will  penetrate  the  healthy,  unbroken 
cutaneous  covering  of  man  under  natural  conditions.  When  pus  bac- 
teria are  vigorously  rubbed  into  the  skin,  especially  when  incorporated 
in  a  salve,  impetigo,  furunculosis  and  even  abscess  formation  may 
result.  Experimental  infection  of  the  lower  animals  has  been  induced 
in  a  similar  manner  with  plague,  glanders,  anthrax,  tuberculosis  and 
recurrent  fever.  The  plague  bacillus  may  penetrate  the  unbroken  and 
unshaven  skin  of  the  guinea-pig  and  cause  general  infection.  The 
protection  afforded  by  the  skin  is  wholly  mechanical.  Infection 
through  the  skin  may  result:  (a)  from  the  bites  of  animals,  as  rabies 
from  the  bite  of  the  dog;  (b)  from  the  bites  of  insects,  as  malaria  and 
yellow  fever,  transmitted  by  mosquitoes,  and  plague  and  other  dis- 
eases transmitted  by  fleas  and  possibly  by  other  insects;  (c)  from 
wounds,  as  syphilis,  tuberculosis,  diphtheria,  tetanus,  pus  infections, 
et  cetera. 

The  Eye. — Local  infection  of  the  conjunctiva  is  a  common  acci- 
dent. Gonorrheal  infection  is  the  most  common  cause  of  ophthalmia 
neonatorum.  Primary  anthrax,  tuberculosis,  diphtheria  and  syphilis 
in  the  eye  have  been  observed.  Animals  have  been  inoculated  through 
normal  eyes  with  glanders,  plague  and  rabies. 

The  Nose. — Notwithstanding  the  marked  germicidal  character  of 
the  nasal  secretions,  this  organ  furnishes  lodgment  for  many  bacteria 
and  is  the  seat  of  primary  glanders  and  leprosy.  Flexner  has  induced 
poliomyelitis  in  apes  by  inoculating  the  nasal  mucosa  with  the  filterable 
virus,  and  a  minimal  quantity  of  a  plague-bacillus  culture  placed  in 
the  nose  of  a  rat  leads  to  general  infection. 

The  Mouth. — The  pavement  epithelium  of  the  normal  mouth  fur- 
nishes a  fairly  good  mechanical  protection  against  the  local  introduc- 


36  AVENUES    OF    INFECTION 

tion  of  bacteria  into  the  lymph  and  blood,  but  this  cavity  does  not 
receive  the  sanitary  attention  it  should.  Tartar  is  permitted  to  accu- 
mulate about  the  teeth  and  cause  atrophy  of  the  gums.  Particles  of 
food  lodge  between  and  about  the  teeth  and  furnish  suitable  material 
for  the  growth  of  bacteria.  Carious  teeth  are  neglected  and  ports  of 
entry  are  directly  opened  up.  Normal  saliva  has  a  distinct  bacteri- 
cidal action,  but  this  is  without  practical  effect  on  the  pneumococcus, 
the  bacilli  of  diphtheria  and  tuberculosis,  the  spirochete  of  syphilis  and 
the  organism  of  actinomycosis.  The  crypts  of  the  tonsils  offer  places 
for  the  lodgment  and  growth  of  bacteria,  and  from  these  localities 
some  of  them  find  their  way  into  the  lymph  and  blood.  Some  hold 
that  tuberculosis  frequently  has  its  primary  location  in  the  tonsils 
from  which  it  passes  through  the  lymph  vessels  to  the  apices  of 
the  lungs. 

Many  pathogenic  bacteria  pass  through  the  nose  and  mouth  with- 
out causing  local  infection.  It  is  not  pleasant  to  state,  but  it  is  true 
that  much  which  is  discharged  from  the  bowels  of  one  goes  into  the 
mouth  of  another.  This  may  be  by  short  or  long  circuit,  but  the 
result  is  likely  to  be  unfortunate  in  either  case.  We  drink  water 
infected  with  typhoid  discharges  and  milk  drawn  with  unclean  hands, 
and  polluted  with  the  excrement  of  man  and  beast.  We  enjoy  fruits 
and  vegetables  from  orchards  and  gardens  strewn  with  filth.  We  eat 
bread  and  meat  handled  without  gloves  by  baker  and  butcher,  and 
for  all  of  this  we  pay  heavy  toll,  as  is  shown  by  the  morbidity  and 
mortality  statistics. 

The  Lungs. — There  has  been  much  discussion  whether  tubercu- 
losis is  most  frequently  acquired  by  inhalation  or  by  deglutition.  Ani- 
mals have  been  experimentally  infected  by  both  of  these  avenues  by 
numerous  investigators  from  Villemin  down  to  the  present  day,  but 
the  opponents  of  the  inhalation  theory  say  that  even  when  bacilli  are 
drawn  with  the  air  through  the  nose  or  mouth,  they  are  deposited  in 
the  pharynx  and  are  swallowed.  The  reply  to  this  is  that  colored  bits 
of  dust  when  inhaled  may  be  carried  directly  to  the  apices  of  the  lungs 
where  they  may  be  recognized.  Furthermore,  attention  is  called  to 
the  inhalation  of  coal  dust  by  miners  and  the  resulting  condition  of 
the  lungs,  known  as  anthracosis.  The  dog  is  quite  readily  infected 


AVENUES    OF    INFECTION  37 

with  tuberculosis  by  inhalation,  rarely  or  not  at  all  by  feeding.  The 
number  of  bacilli  necessary  to  infect  a  guinea-pig  by  inhalation  is 
less  than  one  one-thousandth  of  that  necessary  to  infect  by  feeding. 
When  animals  are  infected  by  inhalation,  the  lesions  can  be  detected 
in  the  lungs  long  before  they  appear  after  feeding. 

The  evidence  that  infection  does  result  from  inhalation  and  that 
the  primary  seat  of  the  infection  is  in  the  apices  of  the  lungs  in  the 
great  majority  of  cases  of  pulmonary  tuberculosis  seems  to  be  indis- 
putable. On  the  other  hand,  it  is  equally  certain  that  infection  may 
develop  by  way  of  the  intestinal  tract.  The  frequency  with  which 
primary  tuberculosis  due  to  the  bovine  bacillus,  occurs  in  the  abdom- 
inal organs  of  children  leaves  no  room  to  question.  The  contention  of 
Koch  that  infected  milk  might  be  neglected  in  our  attempts  to  eradi- 
cate tuberculosis  is  not  supported  by  the  results  of  the  most  thorough 
study  that  has  been  devoted  to  it.  There  is  probably  no  avenue  of 
infection  which  has  not  been  traveled  by  the  bacillus  tuberculosis. 

The  Stomach. — There  is  probably  no  specific  infectious  disease 
which  develops  primarily  in  the  stomach.  Indeed,  the  acid  secretion 
of  this  organ,  while  by  no  means  affording  constant  or  full  protection 
against  intestinal  infection,  undoubtedly  does  much  in  this  direction. 
The  ubiquitous  pus  germ  does  develop  a  gastric  ulcer  now  and  then, 
but  a  more  favored  site  for  this  process  is  in  the  duodenum.  In  the 
intervals  between  digestion  all  kinds  of  harmful  bacteria  may  pass  the 
portals  of  this  viscus  in  safety  and  some  of  them  make  a  successful 
passage  even  when  digestion  is  at  its  height.  It  is  not  wise  to  depend 
on  the  gastric  juice  to  sterilize  our  food. 

The  Intestine. — There  is  general  agreement  that  the  intestine  of 
the  infant  is  more  permeable  to  bacteria  than  that  of  the  adult.  Young 
guinea-pigs  are  easily  infected  with  anthrax  by  feeding,  while  adults 
are  not.  Even  attenuated  cultures  will  infect  a  larger  number  of  the 
young  than  virulent  cultures  will  in  adults.  Like  results  have  been 
reached  by  experiments  with  tuberculosis.  Platte  fed  guinea-pigs  a 
few  days  old  and  adults  with  tubercle  bacilli,  80  per  cent,  of  the  former 
and  30  per  cent,  of  the  latter  became  infected.  Ficker  found  that 
many  bacteria  easily  penetrate  the  intestinal  walls  of  suckling  animals, 
while  they  have  no  effect  on  adults.  These  facts  correspond  with 
observations  on  the  summer  diarrheas  of  infants.  Milk  that  proves 


38  AVENUES    OF    INFECTION 

highly  injurious  to  infants  is  without  harmful  effect  on  adults.  In 
the  fetus  digestion  is  wholly  parenteral  and  it  continues  to  be  partially 
so  during  the  nursing  period,  and  the  intestinal  walls  of  infants  are 
more  permeable  to  both  formed  and  unformed  substances  than  are 
those  of  the  adult.  According  to  von  Behring,  the  great  majority  of 
cases  of  tuberculosis  are  due  to  infection  from  milk  in  infancy.  The 
bacilli  are  retained  in  the  lymphatic  glands  and  invade  other  organs, 
especially  the  lungs,  later  in  life. 

Calmette  teaches  that  in  every  period  of  life  tuberculosis  generally 
enters  the  body  through  the  intestinal  walls  where  it  leaves  no  lesion 
and  from  which  it  travels  to  other  organs.  It  has  been  shown  that  the 
tubercle  bacillus  may  pass  through  the  intestinal  walls  without  leaving 
any  recognizable  lesion,  but  it  is  not  so  certain  that  this  is  the  usual 
port  of  entry.  Even  in  the  adult,  the  intestine  seems  to  be  the  most 
vulnerable  point  in  bacterial  invasion.  It  is  the  exclusive  port  of 
entry  for  cholera,  dysentery  and  typhoid.  The  most  virulent  cholera 
bacillus  injected  under  the  skin  in  amounts  which  would  fatally  infect 
by  the  intestine,  would  be  without  serious  effect.  The  list  of  animal 
infections,  which  are  essentially  intestinal,  embraces  anthrax,  chicken 
cholera,  the  hemorrhagic  septicemias,  hog  cholera,  and  mouse  typhoid. 

It  is  a  noteworthy  fact  that  in  experimental  infection  by  feeding, 
larger  numbers  of  bacilli  must  be  employed  than  can  possibly  be 
required  in  natural  infection.  It  has  been  inferred  from  this  that  in 
natural  infection  the  intestinal  conditions  must  be  especially  favorable 
to  the  multiplication  of  the  organisms.  This  has  led  to  the  assumption 
that  slight  intestinal  disturbances  predispose  to  typhoid  and  other 
intestinal  infections.  This  was  carefully  investigated  by  the  board 
which  studied  typhoid  fever  among  our  soldiers  in  1898,  and  was 
found  to  be  without  support.  Soldiers,  who  were  frequently  on  sick 
report  with  diagnoses  of  gastric  catarrh,  intestinal  indigestion,  etc., 
furnished  actually  a  smaller  percentage  of  typhoid  fever  than  those 
who  had  not  been  on  sick  report  for  any  cause.  Moreover,  many  of 
the  short  and  intermittent  disturbances,  under  a  variety  of  diagnoses, 
were  found  by  the  Widal  test  to  be  typhoid  fever.  Some  have  claimed 
that  the  normal  intestine  is  not  easily  traversed  by  bacteria,  but  the 
difficulty  in  this  is  to  know  when  the  intestnial  walls  are  in  a  healthy 
condition  and  when  they  may  have  suffered  slight  injuries. 


CHAPTER    V 


TUBERCULOSIS 

History. — That  the  people  of  ancient  Egypt  were  afflicted  with 
tuberculosis  has  been  demonstrated  by  an  examination  of  the  bones  of 
mummies.  We  have  no  means  of  estimating  the  extent  of  this  disease 
among  these  people.  The  writings  of  the  great  Greek  physician,  Hip- 
pocrates, show  that  he  was  quite  familiar  with  various  forms  of  tuber- 
culosis. The  period  of  the  Roman  and  Byzantine  Empires  added  noth- 
ing to  the  knowledge  of  the  ancients  on  this  subject.  During  the 
seventeenth  and  eighteenth  centuries  there  was  much  discussion  con- 
cerning tuberculosis,  but  no  experimental  investigation  into  its  nature. 

In  the  seventh  decade  of  the  nineteenth  century,  Villemin,  who 
should  be  regarded  as  the  founder  of  modern  knowledge  of  tubercu- 
losis, conducted  a  series  of  exact  experiments  which  settled  for  all 
time  disputes  concerning  the  contagiousness  of  this  disease.  He  inocu- 
lated many  and  varied  animals  in  diverse  ways  with  the  sputum  and 
other  products  from  tuberculous  lesions  in  men  and  cattle,  and  in 
all  developed  tuberculosis.  He  established  not  only  the  unity  of  the 
various  (tuberculous  manifestations  in  man  but  demonstrated  the 
existence  of  tuberculosis  in  cattle.  He  went  further  and  showed  that 
certain  nodular  diseases,  which  had  been  confounded  with  tuberculosis, 
were  distinct  from  it.  He  found  that  the  inoculation  of  animals  with 
other  than  tuberculous  products  did  not  lead  to  the  development  of 
this  disease.  He  overthrew  the  theory  of  heredity  in  this  disease  and 
established  the  fact  that  it  does  not  result  from  colds  or  other  ills. 
He  went  so  far  as  to  suggest  house  infection  as  an  important  factor 
in  the  dissemination  of  the  disease.  Men  who  tried  to  contradict  the 
findings  of  Villemin  experimentally,  confirmed  him  in  practically  every 
detail. 

In  1882,  Koch,  after  long  and  patient  studies  succeeded  in  isolating 
the  specific  bacillus,  growing  it  in  pure  culture,  and  demonstrating  its 
pathogenicity. 


40  TUBERCULOSIS 

The  Bacillus. — The  specific  causal  agent  of  tuberculosis  is  a  rod- 
like  organism  whose  length  varies  from  one-fourth  to  one-half  the 
diameter  of  a  red  blood  corpuscle  (1.23  to  4.12  of  a  micron).  It  is 
slender  and  non-motile.  It  was  formerly  believed  that  this,  like  other 
bacteria,  should  be  classed  among  microscopic  plants,  but  the  most 
exact  chemical  studies  have  failed  to  show  the  presence  of  cellulose  in 
their  structure.  This  organism  does  not  take  the  ordinary  basic 
aniline  stains  readily,  but  when  treated  with  certain  stains,  such  as 
carbol-fuchsin,  and  heated,  it  stains  deeply  and  retains  the  color  even 
after  washing  with  dilute  mineral  acid.  For  this  reason  it  is  known 
as  an  acid-fast  bacillus  and  it  has  been  found  that  this  group  contains 
a  number  of  micro-organisms  whose  relationship  has  been  a  matter  of 
great  interest.  By  special  staining,  tubercle  bacilli  are  easily  detected 
in  sputum  and  other  excretions  from  tubercular  lesions. 

There  is  still  some  discussion  whether  or  not  this  bacillus  forms 
spores.  The  low  temperature  at  which  it  is  destroyed  and  the  fact 
that  it  is  speedily  killed  by  sunlight  renders  spore  formation  highly 
improbable.  In  old  cultures,  branched  forms  are  occasionally  seen. 
The  tubercle  bacillus  contains  large  amounts  of  fat  and  wax  and  it  is 
probable  that  these  protect  this  organism  from  the  destructive  action  of 
the  secretions  of  the  body  cells.  It  has  been  a  parasite  for  so  long  that 
it  has  developed  this  method  of  protecting  itself.  It  grows  slowly  both 
on  artificial  media  and  in  the  animal  body.  It  is  not  its  purpose 
to  kill  its  host  but  to  feed  on  him  as  long  as  possible.  Unaided  it 
seldom  does  kill,  but  the  necrotic  tissue  caused  by  its  growth  forms  a 
suitable  medium  for  the  lodgment  and  growth  of  other  bacteria  and 
tuberculosis  usually  terminates  as  the  result  of  a  mixed  infection.  So 
long  as  the  infection  is  unmixed,  the  progress  of  the  disease  is  slow. 
As  a  rule,  there  is  no  sputum  until  the  infection  becomes  a  mixed  one ; 
consequently  when  one  waits  for  a  diagnosis  of  this  disease  until  the 
bacilli  are  found  in  the  sputum,  he  waits  too  long.  The  physician  of 
thirty  years  ago  believed  tuberculosis  an  incurable  disease,  because  at 
that  time  he  could  not  make  a  diagnosis  until  there  was  a  troublesome 
cough  with  much  expectoration,  marked  emaciation  and  a  long-con- 
tinued hectic  fever.  All  patients  that  reached  this  stage  died.  After 
Koch's  discovery  of  the  bacillus,  diagnosis  had  to  await  the  detection 
of  this  organism  in  the  sputum.  Again,  it  was  too  late.  With 


TUBERCULOSIS  41 

improved  methods  the  disease  can  be  recognized  in  most  instances 
while  it  is  still  an  unmixed  infection  and  amenable  to  proper  treat- 
ment. 

The  behavior  of  the  bacillus  outside  the  animal  body  is  a  matter  of 
great  importance  in  attempting  the  restriction  of  this  disease.  For- 
tunately, under  ordinary  conditions,  the  tubercle  bacillus  does  not 
multiply  outside  the  animal  body.  It  is  rapidly  overgrown  and  starved 
out  by  saprophytic  organisms.  It  has  been  a  parasite  so  long  that  the 
range  of  temperature  at  which  it  will  multiply  is  limited.  Even  in  pure 
cultures,  protected  from  other  organisms  and  provided  with  an  abun- 
dance of  suitable  food,  it  grows  but  slowly  at  a  temperature  only  a 
few  degrees  below  that  of  the  body.  It  needs  oxygen  and  when  the 
supply  of  this  element  is  short,  growth  is  slow. 

However,  the  practical  question  is,  How  long  will  it  retain  vitality 
and  virulence  outside  the  body?  Multiplication  as  a  saprophyte  is 
under  ordinary  conditions  not  at  all  probable,  but  how  long  will  the 
organism  thrown  off  from  the  body  in  the  sputum  remain  a  source 
of  danger?  This  depends  on  many  conditions.  A  mass  of  sputum 
deposited  on  a  glass  plate  and  allowed  to  stand  at  ordinary  room  tem- 
perature and  in  diffuse  light  may  contain  virulent  bacilli  for  six 
months.  When  the  sputum  is  spread  on  a  plate  in  a  very  thin  layer 
and  submitted  to  the  direct  sunlight,  only  a  few  hours  are  necessary 
to  destroy  its  virulence;  when  only  placed  near  a  window,  days  are 
necessary,  and  sputum  deposited  on  carpets,  rugs,  bedding,  handker- 
chiefs, clothing,  etc.,  may  retain  its  virulence  for  months.  Sputum 
on  walks  and  floors  dries  and  is  scattered  by  winds  and  drafts  and 
may  be  inhaled  or  deposited  on  food.  The  fly  may  carry  the  organism 
to  food.  Heat  immediately  kills  the  tubercle  bacillus  when  suspended 
in  water  or  milk  on  boiling.  Lower  temperatures  must  be  maintained 
for  longer  periods  of  time.  According  to  Forster  the  following  Centi- 
grade temperatures  must  be  continued  for  the  periods  mentioned  in 
order  to  be  effective:  55  for  four  hours;  60  for  one  hour;  65  for 
fifteen  minutes;  70  for  ten  minute;  80  for  five  minute;  90  for  two 
minutes;  95  for  one  minute. 

Milk  should  be  boiled  at  least  three  minutes  to  insure  the  destruc- 
tion of  this  bacillus.  In  thoroughly  baked  or  roasted  meat  the  bacilli 
are  destroyed,  but  in  the  rare  portions  they  may  retain  their  vitality. 


42  TUBERCULOSIS 

Dry  heat  must  be  carried  to  a  higher  degree  or  continued  for  a  longer 
time.  Low  temperatures  are  without  effect.  On  account  of  their  fat 
and  wax  content  tubercle  bacilli  are  highly  resistant  to  disinfectants. 
Mercuric  chlorid  1 :500  and  5  per  cent,  phenol  (carbolic  acid)  are  not 
efficient  in  the  sterilization  of  sputum  even  when  the  contact  continues 
for  twenty-four  hours.  The  ordinary  gaseous  disinfection  of  rooms 
with  formaldehyd  is  unreliable  in  case  of  infection  with  this  bacillus. 
Sputum  from  the  tuberculous  should  be  burned. 

The  Bovine  Bacillus. — It  has  been  shown,  largely  through  the  work 
of  Theobald  Smith,  that  the  human  and  bovine  tubercle  bacilli  are  not 
identical.  They  show  certain  well-marked  and  characteristic  differ- 
ences in  shape,  size,  rapidity  and  manner  of  growth,  in  response  to 
stains  and  in  pathogenicity.  Some  years  ago  Koch  announced  that  in 
the  crusade  against  tuberculosis  in  man  we  can  afford  to  neglect  milk 
as  a  causative  agent.  This  assertion  led  to  much  investigation  into 
the  resemblances  and  differences  between  these  varieties  of  the 
tubercle  bacillus.  With  the  cultural  and  tinctorial  differences  we  need 
not  concern  ourselves  at  present. 

Cattle  are  highly  resistant  to  infection  with  the  human  variety. 
Cattle  have  been  fed  for  months  with  large  quantities  of  the  human 
bacillus  without  developing  an  infection.  Some  of  the  material 
accumulates  in  the  mesenteric  glands  and  undergoes  calcification  but 
the  animal  does  not  develop  tuberculosis.  In  ordinary  infecting  doses, 
intravenous  injection  is  without  effect.  With  larger  amounts  the  ani- 
mal may  be  poisoned  as  might  result  from  similar  treatment  with  any 
one  of  a  number  of  foreign  proteins.  The  human  bacilli  when  thus 
injected  into  a  cow  may  live  for  months  and  may  be  detected  in  the 
milk.  Intraperitoneal  injections  are  without  effect  and  the  same  is 
true  of  those  given  subcutaneously,  except  that  large  quantities  may 
cause  a  local  inflammation  and  this  may  extend  to  neighboring  glands. 
Inhalation  is  without  effect.  It  is  safe  to  say  that  cattle  are  free  from 
the  possibility  of  being  infected  with  tuberculosis  from  man. 

The  guinea-pig  is  highly  susceptible  to  both  varieties,  but  the 
bovine  kills  it  quicker.  The  human  variety  is  uncertain  in  its  action 
on  rabbits.  If  it  develops  at  all,  it  does  so  slowly  and  as  a  rule 
requires  some  weeks  and  possibly  months  to  cause  death.  On  the 


TUBERCULOSIS  43 

other  hand,  this  animal  succumbs  in  most  instances  in  about  three 
weeks  to  the  bovine  variety.  Intravenous,  intraperitoneal,  intraocular 
and  subcutaneous  inoculations  result  in  generalized  fatal  tuberculosis. 

Cattle,  which  as  we  have  seen  are  highly  resistant  to  the  human 
variety,  succumb  readily  to  the  bovine,  whatever  the  method  of  inocu- 
lation. Calves  fed  on  pure  cultures  or  on  the  milk  of  tuberculous 
cows  speedily  develop  the  disease,  which  usually  begins  in  the  forma- 
tion of  ulcers  in  the  upper  intestine  and  extends  to  the  mesenteric, 
lymphatic  and  retropharyngeal  glands.  Infection  may  result  from  a 
single  feeding.  Calves  from  tuberculous  cows  are  free  from  infection, 
but  one  nursing  from  the  mother  may  infect.  The  inhalation  of  a 
very  minute  portion  (0.01  mg.)  of  a  pure  culture  is  followed  by  the 
development  of  pulmonary  tuberculosis. 

Sheep,  hogs  and  goats  are  highly  susceptible  to  the  bovine  variety, 
much  less  so  to  the  human. 

It  seems  safe  to  say  that  tuberculosis  among  our  domestic  animals 
results  generally  from  infection  with  the  bovine  rather  than  the  human 
variety.  However,  some  facts  need  to  be  stated.  Tuberculosis  is 
common  among  chickens  and  it  is  quite  natural  to  suppose  that  these 
animals  become  infected  by  picking  up  human  or  bovine  material,  but 
experiments  show  that  chickens  are  immune  to  both  these  varieties. 
Feeding,  intravenous  and  subcutaneous  inoculations  of  these  varieties 
do  not  develop  tuberculosis  in  chickens.  The  bacilli  retain  their  vital- 
ity in  these  fowls  for  a  long  time  but  fail  to  develop  tuberculosis  in 
the  hosts,  as  has  been  demonstrated  by  inoculation  of  susceptible 
animals,  such  as  the  guinea-pig.  Apes  seem  to  be  equally  susceptible 
to  the  human  and  bovine  varieties. 

Having  ascertained  that  our  domestic  animals  do  not  run  great 
risk  in  being  infected  with  the  human  variety,  let  us  see  what  danger 
there  is  to  man  from  infection  with  the  bovine  variety.  Is  it  wise  to 
follow  the  advice  of  Koch  and  neglect  milk  as  a  factor  in  the  causation 
of  tuberculosis  in  man  ?  This  important  question  has  been  investigated 
in  this  country  by  Park  and  Krumwiede,  by  an  English  commission, 
by  two  German  commissions,  and  by  many  individuals  in  various  parts 
of  the  world.  In  1,441  deaths  from  tuberculosis  in  man,  the  variety 
of  the  bacillus  has  been  determined.  In  117  of  these  (8.1  per  cent.) 
the  bovine  variety  alone  has  been  found.  In  seven  cases  (0.5  per 


44  TUBERCULOSIS 

cent.)  the  infection  has  been  found  to  be  a  mixed  one,  both  varieties 
being  present.  This,  however,  does  not  tell  the  whole  story. 

In  pulmonary  tuberculosis  in  adults  the  bovine  variety  is  rare  (4 
cases  out  of  732) .  In  tuberculosis  of  the  bones  and  joints,  at  all  ages,  the 
bovine  variety  occurs  more  frequently  (5  cases  out  of  98).  In  menin- 
geal  tuberculosis  at  all  ages  the  frequency  is  still  greater  (3  cases  out 
of  32).  In  general  tuberculosis  at  all  ages  there  is  a  further  increase 
(33  cases  out  of  172).  In  tuberculosis  of  the  glands  of  the  neck,  the 
proportion  is  still  higher  (45  cases  out  of  157).  In  tuberculosis  of 
the  abdominal  organs  the  presence  of  the  bovine  variety  reaches  its 
highest  point  (30  cases  out  of  99). 

When  we  study  the  proportion  of  the  two  varieties  in  adults  and 
in  children,  we  get  more  practical  information.  In  children  23.8  per 
cent,  of  generalized  tuberculosis,  40  per  cent,  of  tuberculosis  of  the 
cervical  glands  and  49  per  cent,  of  tuberculosis  of  the  abdominal 
organs  are  due  to  infection  with  the  bovine  variety.  It  is  quite  natural 
that  the  greater  number  of  cases  of  bovine  tuberculosis  should  be 
found  among  children.  These  figures  demonstrate  that  the  character 
of  the  milk  cannot  be  neglected  with  safety  in  the  crusade  against 
tuberculosis.  At  the  same  time,  they  show  that  the  chief  source  of 
infection  in  man  is  the  human  variety  and  that  as  a  rule  tuberculosis  is 
transferred  from  man  to  man. 

The  Avian  Type. — The  barnyard  fowl  is  frequently  tuberculous. 
Much  of  the  poultry  that  comes  to  market,  when  properly  inspected, 
shows  enlarged  livers  filled  with  yellowish  tuberculous  nodules.  This 
variety  of  the  tubercle  bacillus  can  be  distinguished  morphologically 
and  culturally  from  other  forms.  Chickens  are  easily  infected  by 
feeding,  developing  intestinal  and  hepatic  tuberculosis  and  loss  of 
weight.  Intravenous  injection,  even  of  a  minute  quantity,  leads  to 
rapid  emaciation  and  death  may  result  before  macroscopical  changes 
are  in  evidence.  In  less  rapid  cases  the  liver  shows  the  characteristic 
enlargement  and  nodules.  Intraperitoneal  and  intramuscular  inocula- 
tions are  slower,  but  in  time  develop  the  disease.  Ducks  and  pigeons 
may  be  infected,  but  in  nature  the  disease  is  much  less  frequent  in 
these  than  in  chickens. 

The  testimony  concerning  the  susceptibility  of  the  guinea-pig  to 
this  variety  of  the  tubercle  bacillus  is  conflicting.  Evidently  it  is  less 


TUBERCULOSIS  45 

than  that  shown  by  this  animal  to  either  the  human  or  bovine  variety. 
Rabbits  seem  to  be  more  susceptible,  though  typical  tubercular  nodules 
are  not  always  developed  in  these  animals,  many  dying  from  septi- 
cemia.  Calves  fed  on  the  avian  bacillus  may  develop  local  tubercu- 
losis in  the  intestine  and  mesenteric  glands,  but  this  seems  to  have  little 
effect  on  the  growth  and  health  of  the  animal.  Subcutaneous  injec- 
tions in  cattle  cause  an  inflammatory  reaction  which  may  extend  to 
neighboring  glands,  but  fail  to  develop  general  tuberculosis.  In  the 
studies  of  the  varieties  of  tubercle  bacilli  found  in  man,  already 
referred  to,  three  cases  of  infection  with  avian  bacilli  were  found. 
However,  it  is  not  certain  that  these  people  were  not  also  infected 
with  one  of  the  other  varieties.  In  at  least  three  other  cases  the  avian 
bacillus  has  been  found. 

That  the  flesh  of  tuberculous  fowls  frequently  comes  to  the  table 
is  beyond  dispute.  The  methods  of  cooking  probably  kill  all  the  bacilli. 
Besides,  the  appearance  of  the  liver  is  so  striking  that  this  organ  is 
removed  before  dressed  fowl  comes  under  the  eye  of  the  consumer. 
No  observant  cook  could  overlook  so  abnormal  an  organ  as  the  liver 
in  a  well-developed  case  of  tuberculosis  gallinaceus. 

The  Piscidian  Variety. — Fish,  amphibians  and  reptiles  are  suscep- 
tible to  a  form  of  tuberculosis  due  to  a  variety  of  the  bacillus  which 
is  not  capable  of  growth  at  the  temperature  of  the  body  in  mammalians 
and,  therefore,  cannot  be  a  source  of  infection  in  man.  One  would  not 
knowingly  eat  a  tuberculous  fish,  but  if  he  unknowingly  does  so, 
tuberculosis  will  not  result. 

Other  Acid-Fast  Bacilli. — There  are  several  well-known  and  thor- 
oughly studied  saprophytic  bacteria  which  have  a  close  resemblance 
to  tubercle  bacilli  in  their  reactions  towards  certain  stains.  They  are 
not  easily  stained  by  ordinary  dyes,  but  when  thoroughly  stained  with 
carbol-fuchsin  or  similar  agents  the  color  is  not  removed  by  washing 
with  dilute  mineral  acid.  These  organisms  are  classed  with  tubercle 
bacilli  as  "acid-fast"  organisms.  These  have  been  especially  studied 
by  Moeller  who  has  defined  several  species  or  varieties.  One  point  of 
interest  is  that  they  may  be  mistaken  for  tubercle  bacilli.  This  is  likely 
to  occur  because  one  of  them  is  found  on  timothy  hay  and  is  known  as 
"Moeller's  timothy"  bacillus  and  another  is  found  in  cow  dung.  So 
far  as  they  have  been  tested  they  are  not  pathogenic  to  any  animal. 


46  TUBERCULOSIS 

Whether  or  not  all  of  these  acid-fast  organisms  have  been  evolved 
from  a  common  ancestor  is  a  fruitful  field  for  theoretic  discussion. 
No  one  has,  as  yet,  converted  one  of  these  into  a  pathogenic  organism, 
though  this  has  been  tried  by  frequent  passage  through  animals.  They 
may  produce  local  reactions  which  closely  resemble  those  developed  by 
inoculation  with  one  of  the  pathogenic  types,  but  they  do  not  cause 
general  tuberculosis.  That  their  cellular  structure  is  similar,  chem- 
ically at  least,  to  that  of  the  virulent  types  is  shown  by  the  following: 
(1)  their  similar  behavior  toward  stains,  (2)  their  local  effects,  (3) 
animals  sensitized  to  one  of  these  saprophytic  forms  are  partially  sensi- 
tized to  the  virulent  types. 

Many  attempts  have  been  made  to  convert  one  virulent  type  into 
another.  The  human  and  avian  types  have  been  carried  through  many 
cows  and  the  human  and  bovine  varieties  have  been  carried  through 
chickens.  The  results  of  this  work  have  been  by  no  means  uniform. 
Some  investigators  have  convinced  themselves  that  transformation 
from  one  type  to  another  is  easily  and  quickly  secured,  while  another 
man,  equally  competent,  repeats  the  work  and  is  sure  that  such  a 
transformation  never  results.  The  conditions  under  which  such  work 
must  be  done  render  mistakes  easily  possible  and  to  obtain  satisfactory 
and  convincing  proof  seems  quite  impossible. 

For  instance,  one  man  attempts  to  carry  the  human  type  succes- 
sively through  many  calves  in  order  to  transform  it  into  the  bovine 
variety.  At  last  he  inoculates  a  calf  and  later  finds  in  that  animal  a 
typical  bovine  organism.  The  experimenter  claims  that  he  has  dem- 
onstrated a  transformation,  but  his  critic  says  the  tuberculosis  found 
in  the  last  calf  is  not  a  result  of  the  inoculation,  but  is  a  true  bovine 
tuberculosis  from  a  wholly  different  source. 

One  of  the  most  convincing  experiments  in  favor  of  a  transforma- 
tion in  type  is  that  of  Nocard.  He  placed  a  culture  of  the  human 
type  in  a  collodion  sack  and  introduced  the  sack  into  the  abdominal 
cavity  of  a  chicken;  after  some  weeks  he  transferred  the  sack  to  the 
abdominal  cavity  of  a  second  chicken  and  after  another  interval  to  a 
third.  After  this  he  found  that  the  type  had  been  changed  to  avian. 

This  has  been  repeated  by  two  other  investigators,  one  of  whom 
confirms  and  the  other  denies  Nocard's  claim.  The  solution  of  the 
question  concerning  the  relation  of  the  saprophytic  acid-fast  bacilli  to 


TUBERCULOSIS  47 

the  pathogenic,  and  of  the  different  types  of  the  latter  to  one  another 
must  await  future  investigations. 

Avenues  of  Infection. — The  most  important  of  these  lies  in  the 
respiratory  organs.  The  nose  serves  as  a  filter  and  its  secretion  is 
germicidal.  Besides,  there  is  free  exit  for  accumulations,  and  the  ease 
with  which  sneezing  is  induced  by  slight  irritation  and  air  can  be 
forced  through  it  by  blowing  the  nose,  tends  to  keep  this  cavity  clean. 
The  nose  is  seldom,  probably  never  except  in  wounds  or  abrasions  of 
the  mucous  membrane,  the  seat  of  a  primary  tuberculous  infection.  It 
may  be  secondarily  involved  in  tuberculosis  of  the  lungs.  Mouth 
breathing  increases  the  chances  of  infection.  The  retronasal  pharynx 
is  less  easily  kept  clean  and  is  more  frequently  the  site  of  infection, 
but  this  also  is  generally  secondary.  The  tonsils  frequently,  even  in 
non-tuberculous  persons,  are  found  to  contain  tubercle  bacilli. 
Whether  these  glands  do  more  than  retain  the  bacilli  is  not  known. 
The  larynx  is  more  frequently  the  seat  of  primary  infection,  and  is 
involved  sooner  or  later  in  about  one-fourth  the  cases  of  pulmonary 
tuberculosis. 

Infection  of  the  trachea  and  large  bronchi  is  rare.  The  primary 
seat  of  most  cases  of  pulmonary  tuberculosis  is  in  one  of  the  apices 
of  the  lungs.  This  is  due  to  the  fact  that  bacilli  having  reached  these 
localities  are  not  easily  dislodged.  This  is  true  of  inhaled  particles 
of  any  kind  and  when  these  are  hard  and  rough  they  cause  slight 
wounds  which  form  suitable  places  for  the  entrance  and  growth  of  the 
bacilli.  This  accounts  for  the  greater  susceptibility  to  tuberculosis  of 
those  engaged  in  dusty  occupations,  especially  marble  cutters  and 
steel  filers. 

The  next  most  favorable  avenue  for  tuberculous  inoculation  is 
through  the  digestive  organs.  Carious  teeth  provide  a  port  of  entry 
and  the  infection  introduced  in  this  manner  finds  its  way  into  the 
adjacent  glands.  Sore  and  raw  gums  due  to  deposits  of  tartar  and 
the  fermentation  of  lodged  particles  of  food,  offer  additional  points 
of  entry  not  only  for  the  tubercle  bacillus  but  for  other  pathogenic 
organisms.  These  facts  emphasize  the  importance  of  oral  hygiene, 
which  is  greatly  neglected  in  both  children  and  adults.  Tubercle 
bacilli  have  been  detected  in  carious  teeth,  in  tartar  and  in  the  coating 


48  TUBERCULOSIS 

on  the  tongue.  Demme  reports  four  childdren  who  were  infected  by 
a  nurse  who  was  accustomed  to  put  the  spoonful  of  food  to  her  lips 
and  tongue  in  order  to  test  its  temperature  in  feeding  the  children  and 
I  have  seen  a  mother  chew  the  food  given  her  children.  The  esoph- 
agus and  stomach  are  seldom  or  never  the  sites  of  tuberculous 
lesions.  The  food  quickly  passes  the  esophagus  and  the  acidity  of 
the  stomach  contents  protects  that  organ.  In  most  cases  of  infection 
by  way  of  the  alimentary  tract  the  bacilli  find  lodgment  in  the  small 
intestine,  through  the  walls  of  which  they  may  pass  without  leaving  a 
recognizable  lesion. 

There  are  three  forms  of  tuberculous  skin  affection,  tuberculosis 
verrucosa,  lupus  and  tuberculous  ulcer.  These  may  be  due  to  scratch- 
ing with  infected  finger  nails,  cuts  with  infected  knives  or  wounds 
with  other  infected  instruments.  Tuberculosis  of  the  skin  is  especially 
frequent  among  butchers.  A  general  infection  may  result  through 
the  skin.  Several  cases  of  infection  through  the  rite  of  circumcision 
have  been  reported  and  medical  students  have  been  infected  in  dissect- 
ing tuberculous  bodies  and  surgeons  in  doing  operations  and  making 
postmortems.  In  all  these  instances  the  infection  extends  to  the  near- 
est lymph  glands  and  then  on  to  the  next.  The  point  of  entry  may  or 
may  not  show  a  lesion.  Infection  of  the  joints  and  bones  is  always 
secondary. 

Sources  of  Infection. — The  most  abundant  source  of  infection  is 
dried  tuberculous  sputum.  So  long  as  the  sputum  is  moist  it  is  not 
distributed  through  the  air.  When  deposited  on  sidewalks,  the  sputum 
adheres  to  the  feet  or  may  cling  to  the  clothing  and  in  either  case 
is  carried  into  the  house  where  it  becomes  more  dangerous.  The 
greatest  danger  is  in  closed  rooms  in  which  sputum  has  been  deposited 
on  the  floor.  Cornet  made  the  following  experiment  which  illustrates 
how  infection  may  be  spread.  A  carpet  which  had  been  contaminated 
with  infected  sputum  some  days  before  was  spread  on  a  floor.  Cages 
containing  48  guinea-pigs  were  placed  at  different  levels  in  the  room 
and  the  carpet  was  vigorously  swept  with  a  broom  until  the  room  was 
filled  with  a  cloud  of  dust.  Of  the  guinea-pigs  exposed  to  this  dust, 
all  but  one  became  tuberculous.  The  same  investigator  sponged  the 
walls  of  a  room  occupied  by  a  tuberculous  patient  who  expectorated 


PSEUDOTUBERCULOSIS  49 

on  the  floor,  and  the  material  absorbed  by  the  sponge  was  injected 
into  guinea-pigs  with  positive  results. 

Fliigge  has  called  attention  to  the  fact  that  in  coughing,  sneezing 
and  even  in  speaking  the  consumptive  may  eject  an  infected  spray. 
Not  only  is  there  immediate  danger  from  the  inhalation  of  the  spray 
but  subsequent  danger  from  the  dried  droplets  which  may  fall  on  the 
floor  or  furniture.  The  house-fly  walks  in  sputum,  eats  it,  and  subse- 
quently may  feed  on  food,  or  drink  or  even  drown  himself  in  milk. 
As  we  have  seen,  the  milk  of  tuberculous  cows  is  a  source  of  danger, 
especially  to  children.  Cream  and  butter  from  such  milk  may  contain 
tubercle  bacilli.  There  is  less  danger  in  meat  on  account  of  the  cook- 
ing, but  meat  when  made  into  sausage  is  eaten  raw  by  some  people. 

Tuberculosis  is  in  no  proper  sense  an  inherited  disease.  When 
the  mother  suffers  from  general  tuberculosis,  the  placenta  may  be 
involved  and  the  child  may  be  infected  in  utero.  This  is  congenital, 
not  inherited,  tuberculosis,  and  only  a  few  cases  of  this  are  known. 

PSEUDOTUBERCULOSIS 

We  are  indebted  for  our  knowledge  of  this  disease  largely  to 
French  investigators  who  recognized  it  as  early  as  1883.  It  is  desig- 
nated a  tuberculosis  because  in  its  lesions,  the  histologic  changes 
closely  resemble,  though  they  are  not  identical  with,  those  seen  in 
true  tuberculosis.  It  is  caused  by  wholly  different  bacilli,  of  which 
there  are  several  varieties,  and  none  of  these  is  acid-fast.  They  are 
easily  stained,  the  stains  are  easily  washed  out  with  dilute  mineral 
acids  and  the  bacilli  are  destroyed  by  relatively  weak  disinfectants. 
Besides,  the  bacilli  do  not  contain  the  large  amounts  of  fats  and  waxes 
found  in  true  tubercle  bacilli. 

The  most  important  manifestation  of  this  disease  is  in  sheep  and  it 
is  said  that  15  per  cent,  of  these  animals  in  Australia  and  10  per  cent, 
in  Argentina,  as  they  come  to  the  market,  are  infected.  The  bacillus 
which  infects  sheep  is  a  long  (1-3  microns),  non-motile,  non-liquefying 
organism  which  grows  easily  and  abundantly  on  gelatin,  coagulated 
serum  and  agar,  and  in  bouillon.  Unlike  the  tubercle  bacillus,  it 
produces  a  soluble  toxin.  An  antitoxin  has  been  prepared  which  pro- 
tects against  the  toxin  but  not  against  the  bacillus,  and  consequently, 
while  of  great  scientific  interest,  is  of  no  practical  importance  in  pro- 


SO  PSEUDOTUBERCULOSIS 

tection  against  infection.  Sheep  are  supposed  to  acquire  the  infection 
largely  through  feeding. 

As  the  disease  is  slowly  progressive  and  most  sheep  are  slaugh- 
tered, the  condition  is  usually  not  recognized  during  life. 

This  variety  of  the  bacillus  is  pathogenic,  not  only  to  sheep  but, 
experimentally  at  least,  to  goats,  rabbits,  guinea-pigs  and  mice,  but  not 
to  chickens  and  pigeons.  A  second  variety  of  this  organism  is  patho- 
genic to  mice,  especially  to  gray  mice.  It  is  not  known  to  be  patho- 
genic to  any  other  animal.  Bouillon  cultures  of  this  variety  become 
slightly  cloudy  and  deposit  abundant  coffin-lid  crystals  (ammonio- 
magnesium  phosphate). 

A  third  variety  seems  to  be  pathogenic  to  many  rodents  and  may 
cause  epidemics  in  rabbits  and  guinea-pigs.  This  produces  crystals 
in  both  gelatin  and  bouillon  cultures  and  does  not  elaborate  a  soluble 
toxin.  A  fourth  variety  infects  children  and  several  cases  have  been 
reported  by  French  physicians.  The  cat  is  suspected  as  a  carrier. 


CHAPTER    VI 


LEPROSY 

History. — This  disease  prevailed  among  the  Egyptians  as  early  as 
2,400  years  before  Christ.  The  records  show  that  it  existed  in  India 
and  China  at  least  1,000  years  B.  C.  Whether  the  word  leprosy  as 
used  in  the  Old  Testament  was  confined  to  this  disease  or  included 
other  loathsome  conditions,  has  been  a  matter  of  dispute  among 
scholars  and  remains  without  definite  settlement.  Some  say  that  the 
Israelites  became  infected  with  this  disease  in  Egypt  and  the  claim 
is  made  that  on  account  of  the  prevalence  of  this  disease  among  them 
they  were  driven  out  of  that  country.  The  Persian  wars  apparently 
led  to  its  introduction  into  Greece,  and  with  the  Roman  subjugation 
of  Greece  it  was  diffused  over  Italy,  in  parts  of  which  it  had  existed 
long  before  this  time.  During  the  first  and  second  centuries  of  our 
era  it  became  quite  common  in  Italy  and  gradually  spread  over  the 
greater  part  of  Europe.  It  had  become  so  common  and  had  awakened 
so  much  apprehension  in  France  in  the  sixth  and  seventh  centuries 
that  the  segregation  of  lepers  was  begun. 

With  the  general  scientific  awakening  of  the  fifteenth  and  sixteenth 
centuries,  more  attention  was  given  to  the  restriction  of  this  disease. 
It  is  said  that  the  number  of  leprosaria  in  France  reached  1,500  and 
that  in  the  whole  of  Europe  it  was  as  great  as  19,000.  Lepers  were 
generally  known  as  Christ's  poor,  and  the  leprosaria  were  under  the 
special  care  of  the  order  of  St.  Lazarus,  and  were  directed  by  priests, 
who  were  themselves  lepers.  The  attempt  was  made,  and  it  must 
have  been  on  the  whole  successful,  to  segregate  all  lepers  in  these 
institutions.  When  a  leper  went  abroad  he  wore  a  peculiar  garb  and 
at  night  he  carried  a  bell.  Recognized  by  these  signs  he  was  shunned. 
During  the  seventeenth  century  the  number  of  lepers  in  Europe  rap- 
idly decreased  until  the  disease  practically  disappeared,  "except  on  the 
fringe  of  the  continent."  However,  traces  of  it  have  continued,  espe- 
cially in  Norway  and  parts  of  Russia.  It  has  continued  in  Asia  and 
Africa.  Whether  the  North  American  Indians  or  the  Aztecs  of 


52  LEPROSY 

Mexico  were  infected  with  this  disease  in  pre-Columbian  days  is  still 
a  matter  of  dispute,  with  the  evidence  clearly  in  favor  of  the  negative 
side.  Leprosy  was  probably  introduced  into  what  is  now  the  terri- 
tory of  the  United  States  by  slaves  from  Africa  in  the  last  quarter 
of  the  eighteenth  century,  and  first  appeared  in  Florida.  Since  that 
time  and  even  up  to  the  present  there  are  occasional  fresh  importa- 
tions from  Norway,  China,  Russia  and  the  islands  of  the  Pacific. 

Present  Distribution. — This  ancient  disease  is  still  distributed  over 
all  tropical  and  temperate  regions.  There  is  no  nation  wholly  free. 
There  are  colonies  or  nurseries  here  and  there  and  every  century  some 
seed  from  at  least  one  of  these  finds  growth  in  some  other  locality. 
Some  of  these  nurseries  have  been  in  continuous  existence  since  the 
dark  ages.  Such  is  the  colony  at  Bergen  where,  according  to  Hansen, 
there  was  leprosy  as  early  as  the  eleventh  century  and  probably  earlier. 
The  seeds  have  never  been  entirely  destroyed  and  the  number  of  lepers 
fluctuates  with  the  effectiveness  of  restriction.  From  1836  to  1856  the 
number  of  lepers  in  Bergen  multiplied  more  than  three  times.  This 
led  to  stricter  regulations  and  by  1907  the  number  had  fallen  to  about 
two-thirds  of  what  it  was  in  1836.  From  this  nursery  at  Bergen,  seed 
has  been  scattered  to  the  furthermost  parts  of  the  earth  and  daughter 
colonies  have  been  established  in  Russia  and  in  the  United  States. 

The  guess  as  to  the  number  of  lepers  now  living  runs  from  one 
to  two  million.  These  are  mere  guesses  and  it  is  not  probable  that 
the  exact  number  of  lepers  in  any  country  is  known.  Certainly  we 
do  not  know  how  many  there  are  in  the  United  States.  According  to 
Brinkenhoff  there  were,  in  1909,  146  officially  reported  cases,  but  this 
includes  only  50  in  Louisiana  where,  according  to  Dwyer,  there  are 
at  least  300.  Pollitzer  makes  the  number  in  this  country  530  and 
Ashmead  thinks  it  reaches  3,000.  The  former  is  undoubtedly  too  low 
and  the  latter  probably  too  high.  We  should  have  a  national  lepros- 
arium. To  longer  neglect  to  provide  one  is  not  only  short-sighted  but 
well-nigh  criminal.  It  is  true  that  state  laws  provide  that  lepers  shall 
be  isolated,  but  this  is  only  on  paper  and  without  the  possibility  of 
enforcement.  Neither  state  nor  nation  has  any  provision  for  the 
isolation  of  these  unfortunates,  and  the  way  in  which  some  of  them 
have  been  tossed  from  pillar  to  post  is  not  a  credit  to  our  civilization. 


LEPROSY  53 

Even  in  Louisiana  where  there  is  a  state  colony,  isolation  is  not  effec- 
tively carried  out. 

The  Bacillus. — The  bacillus  discovered  by  Hansen  of  Bergen  is 
believed  to  be  the  specific  cause  of  leprosy,  although  all  the  condi- 
tions necessary  to  establish  this  fully  have  not  been  complied  with. 
This  organism  is  a  long  (1.5-6  microns),  slender  (0.2-0.5  micron) 
rod,  which  is  acid-fast  and  belongs  to  the  same  group  as  the  tubercle 
bacillus!  It  takes  fuchsin  and  similar  stains  more  readily  than  the 
tubercle  bacillus  and  loses  the  stain  more  easily  when  washed  with 
dilute  mineral  acid.  However,  these  differences  are  so  slight  and  vary 
so  much  with  different  strains  of  both  organisms,  that  they  do  not 
give  a  means  of  positive  differentiation.  The  leprosy  bacillus  is  oftener 
found  in  bundles  and  these  are  larger  than  those  of  the  tubercle 
bacillus.  This  is  not  always  distinctive,  however.  Much  effort  has 
been  made  to  find  some  certain  method  by  which  the  microscopic  dis- 
tinction between  the  two  organisms  may  be  determined.  An  expert 
in  this  work  may  distinguish  these  in  many  instances,  but  ordinarily 
it  is  not  easy.  The  bacillus  of  leprosy  may  be  mistaken  not  only  for 
the  tubercle  bacillus,  but  it  may  be  confounded  with  nonpathogenic 
acid-fast  organisms,  such  as  the  smegma  bacillus.  The  leprosy  organ- 
ism seems  more  truly  parasitic  than  the  tubercle  bacillus  and  so  far 
it  has  not  been  grown  satisfactorily  on  artificial  media,  unless  the 
method  of  Clegg  be  an  exception.  This  American  investigator  uses 
a  bouillon  to  which  amebas'from  dysenteric  stools  have  been  added. 
This  preparation  is  inoculated  with  leprosy  tissue  and  some  observers 
have  succeeded  in  obtaining  a  growth  which  at  the  last  report  had 
been  carried  to  the  tenth  generation.  Attempts  to  inoculate  the  lower 
animals  with  leprosy  material  have  not  been  convincing.  A  number 
of  men  have  submitted  themselves  to  this  experiment  and  still  the 
result  is  left  in  doubt.  In  several  cases  this  test  has  been  negative. 
In  others  it  has  been  positive,  but  in  all  of  the  latter  the  tested  indi- 
viduals have  been  associated  more  or  less  intimately  with  lepers.  The 
Hawaiian  convict,  who  had  his  choice  between  suffering  the  death 
penalty  and  inoculation,  developed  local  lesions  but  these  soon  dis- 
appeared. For  nearly  two  years  he  remained  apparently  well  and 
then  developed  the  disease,  of  which  he  died  after  four  years.  This 


54  LEPROSY 

test  cannot  be  considered  final,  because  the  disease  had  affected  some 
of  his  family. 

The  fact  that  the  Hansen  bacillus  is  found  in  all  lepers,  when  a 
thorough  examination  is  made,  must  for  the  present  be  accepted  as  a 
justification  of  the  belief  that  it  is  the  causal  agent.  However,  many 
problems  in  the  etiology  of  this  disease  remain  unsolved.  This  bacillus 
may  be  aided  by  some  other  causal  agent  or  it  may  be  infective  only 
in  certain  conditions  or  states  of  health  or  in  certain  deviations  from 
health.  It  seems  safe  to  say  that  the  evidence  available  at  present 
indicates  that  leprosy  is  a  transmissible  disease,  but  that  it  requires 
more  intimate  contact  for  its  transmission  than  most  of  the  other  bac- 
terial affections.  Its  history,  even  when  studied  most  superficially, 
indicates  its  contagiousness.  Such  a  colony  as  that  at  Bergen  has 
brought  it  down  continuously  for  at  least  eight  hundred  years.  When 
a  leper  finds  his  way  into  a  region  where  the  disease  has  never  been 
known,  it  slowly  spreads.  In  this  way,  cases  have  developed  in  Min- 
nesota, Michigan,  Iowa  and  elsewhere  in  this  country.  From  Norway 
the  disease  has  been  transplanted  to  the  Baltic  provinces  of  Russia, 
where  the  number  at  present  is  estimated  at  more  than  one  thousand. 
In  Finland  there  is  a  leprosarium  which  was  established  in  1355  and 
in  1908  it  housed  87. 

Avenues  of  Infection. — Supposing  that  the  disease  first  manifests 
itself  at  the  site  of  inoculation,  there  is  reason  for  believing  that  the 
bacillus  finds  its  entrance  through  wounds  of  the  surface.  It  is  a 
common  observation  in  leprous  countries  that  those  who  go  barefooted 
are  more  frequently  attacked  than  those  who  wear  shoes,  and  that  the 
first  recognizable  lesions  are  on  the  feet.  Two  French  physicians 
report  that  among  2,437  cases  under  their  observation  in  Cochin- 
China,  526  were  general  from  the  start,  550  showed  the  first  lesions  on 
the  feet,  420  on  the  hands,  321  simultaneously  on  feet  and  hands,  and 
337  on  the  face.  It  is  an  old  belief  that  infection  frequently  develops 
in  the  nose.  Heiser  found  nasal  ulceration  in  799  out  of  1,200  cases 
and  others  have  reported  even  larger  percentages.  In  recognizing  this 
disease,  one  of  the  first  things  to  do  is  to  stain  the  nasal  secretion 
of  the  suspected  person  for  the  bacilli.  Among  the  healthy  associated 
with  lepers  the  bacilli  are  frequently  found  in  the  nose.  There  is 


LEPROSY  55 

no  reason  for  thinking  that  it  develops  from  deep  breathing  in  of  the 
bacillus,  because  the  lungs  are  never  primarily  involved. 

The  possibility  of  the  transmission  of  the  disease  through  the 
agency  of  insects  has  been  considered,  but  its  wide  geographical  dis- 
tribution does  not  render  this  view  probable.  The  relation  of  fish  diet 
to  leprosy,  so  earnestly  advocated  by  the  late  Jonathan  Hutchinson,  has 
not  found  wide  support. 


CHAPTER    VII 


ASIATIC    CHOLERA 

History. — We  have  no  positive  knowledge  of  Asiatic  cholera  before 
1816.  It  is  assumed  by  some  that  it  had  long  existed  in  endemic 
form  in  the  region  about  the  delta  of  the  Ganges  and  it  is  reported  to 
have  appeared  in  the  Goa  district  (Portuguese  Settlement)  as  early 
as  1543  and  in  the  Pondicherry  (French  Settlement)  in  1768,  but 
there  is  no  positive  knowledge  of  these  facts.  In  1816  this  infection 
began  its  first  recorded  travels  and  reached  countries  so  remote  that 
it  could  be  regarded  as  pandemic.  The  time  assigned  by  Haeser  to 
the  first  great  excursion  of  this  infection  extended  through  seven 
years  (1816-1823).  It  traveled  slowly  at  that  time,  before  the  gen- 
eral use  of  steam  transportation,  and  did  not  get  beyond  the  confines 
of  Asia  and  Africa.  To  the  east  and  south  it  visited  Borneo,  Java, 
the  Philippines  and  China.  To  the  west  and  north  it  spread  through 
Arabia,  Persia,  Syria,  Egypt  and  Northern  Africa.  It  lingered  in 
various  localities  for  some  years,  after  which  it  was  known  only  in 
its  home  until  1826  when  the  second  visitation  began.  This  continued 
for  eleven  years,  terminating,  according  to  Hirsch,  in  1837.  This 
time  it  spread  over  the  greater  part  of  Europe  and  America.  It  broke 
up  into  parties  which  traveled  different  routes,  some  by  sea  and  some 
by  land.  The  faithful  from  further  India  brought  it  to  Mecca  where 
it  found  ready  but  slow  transportation  to  all  points  of  the  compass. 
Nothing  more  was  known  of  the  infection  outside  its  own  domicile 
until  1846.  The  third  pandemic  reached  the  farthermost  parts  of  the 
earth  and  lasted  until  1862.  It  killed  in  France  alone,  in  1853-54  nearly 
one  hundred  and  fifty  thousand  and  it  pursued  the  gold  seeker  on  his 
way  across  the  plains  to  California.  The  fourth  pandemic  was  well 
in  evidence  by  1864  and  continued  until  1875.  As  the  records  show, 
it  found  114,683  victims  in  Prussia  alone  on  this  trip.  The  fifth  pan- 
demic began  in  1883,  spread  over  the  eastern  hemisphere  and  reached 
New  York  harbor,  but  was  refused  admission.  This  time  the  number 
of  victims  in  European  Russia  alone  is  given  at  800,000.  The  notable 


58  CHOLERA 

outburst  at  Hamburg  belongs  to  this  period.  In  1902  cholera  for  the 
sixth  time  became  pandemic.  It  was  disseminated  by  400,000  pilgrims 
gathered  together  at  Mecca.  Since  that  time  and  up  to  the  present  it 
has  been  found  in  various  parts  of  Europe  and  has  repeatedly  reached 
our  own  shores,  but  has  not  been  permitted  to  gain  a  foothold. 

In  all  these  excursions,  among  all  kinds  and  conditions  of  men, 
in  every  degree  of  civilization,  in  the  tropics  and  amid  the  snow  and 
ice  of  northern  Russia,  in  the  thronged  city  and  in  the  emigrant's 
wagon,  with  high  and  low,  slave  and  master,  wherever  it  has  traveled, 
cholera  has  maintained  its  individuality  and  has  shown  no  modification 
in  manner  of  attack  or  variation  in  the  symptoms  induced  in  its  victims. 
Its  vehicle  of  transport  has  been  man's  body  and  it  has  followed  the 
lines  of  human  travel,  on  foot,  on  horse  or  camel,  by  stage  or  ox 
team,  by  steam,  on  land  and  sea.  The  sick  and  dying  have  scattered 
its  progeny  around  the  world.  The  science  of  preventive  medicine  is 
the  only  detective  who  can  trace  this  criminal,  the  only  officer  who 
can  arrest  it  and  the  only  executioner  who  may  finally  remove  it  for 
all  time  from  the  earth. 

The  Bacillus. — In  1883  the  German  government  sent  a  commission 
with  the  distinguished  bacteriologist,  Robert  Koch,  at  its  head,  first 
to  Egypt  and  then  to  India  to  ascertain  the  cause  of  this  disease.  Many 
months  were  spent  in  the  study  of  the  discharges  of  the  sick,  the  post- 
mortem examination  of  the  dead  and  the  investigation  of  the  food 
and  drinking-water  of  the  infected.  The  result  was  the  discovery  of 
the  infective  agent,  and  this  has  placed  in  man's  hands  the  possibility 
of  completely  eradicating  this  disease.  The  bacillus  is  a  slightly  curved 
rod,  averaging  about  1.5  micron  in  length  and  one-third  this  in  breadth, 
but  with  many  variations.  Frequently,  many  individuals  are  attached, 
end  to  end,  forming  something  like  the  letter  S.  It  is  known  as  the 
comma  bacillus  or  the  cholera  vibrio.  It  is  distinguished  from  similar 
vibrios  by  having  a  single  flagellum  or  whip  at  one  end.  Its  rapid 
motility  in  suspension  is  due  to  this  whip.  Sometimes  the  form  is 
ovoid,  often  much  longer  and  shows  a  long  whip.  It  is  easily  recog- 
nized in  the  stools  by  an  expert  and  the  diagnosis  in  suspected  cases  is 
easy  and  certain.  It  takes  the  ordinary  basic  stains  easily  and  deeply, 
but  in  order  to  stain  the  whip  a  mordant  dye  is  desirable.  It  grows 


CHOLERA  59 

rapidly  on  gelatine  plates  at  22  C.  (71.6  F.),  forming,  within  twenty- 
four  hours,  colonies  visible  as  small  bright  points. 

Under  a  low  power  the  colonies  appear  like  fine  bits  of  glass 
strewn  over  the  gelatine.  They  are  easily  distinguished  from  colonies 
of  Bacterium  coli,  found  in  normal  stools,  by  their  greater  refraction. 
After  forty-eight  hours  the  gelatine  under  and  about  the  colony  begins 
to  liquefy,  forming  a  small  funnel  or  crater  in  the  bottom  of  which 
lies  the  colony.  Old  subcultures  develop  colonies  on  gelatine  plates 
which  are  less  characteristic  than  those  freshly  obtained  from  cholera 
stools.  In  gelatine  stick  cultures  the  bacillus  grows  along  the  line  and 
looks  like  a  white  thread.  Liquefaction  begins  at  the  top  and  extends 
downward  forming  a  funnel-shaped  depression.  Colonies  grown  on 
agar  plates  are  also  quite  characteristic.  On  other  media  it  grows 
quickly,  especially  so  in  alkaline  1  per  cent,  peptone  solution.  The 
cholera  bacillus  does  not  grow  in  the  absence  of  air  and  consequently 
is  known  as  an  obligate  aerobe. 

The  cholera  bacillus  grows  most  abundantly  at  or  a  few  degrees 
above  body  temperature  and  does  not  wholly  cease  to  multiply  until 
the  temperature  is  at  or  below  8  C.  (46.4  F.).  Freezing  does  not 
destroy  it  and  it  retains  its  virulence  after  having  been  frozen  in 
ice  for  several  days.  It  is  quickly  destroyed  by  drying.  A  drop  of  a 
bouillon  culture  placed  on  glass  and  allowed  to  dry  in  the  diffuse 
light  of  a  room  shows  no  growth  when  placed  in  proper  medium  after 
two  hours.  When  exposed  to  direct  sunlight  life  is  destroyed  in  even 
less  time.  This  indicates  that  the  bacillus  does  not  form  spores  and 
that  the  disease  is  not  air  borne. 

Boiling  destroys  the  bacillus  instantly;  at  80  C.  (176  F.)  five  min- 
utes is  long  enough  to  destroy  its  vitality  and  a  temperature  as  low 
as  55  C.  (131  F.)  has  the  same  effect  after  half  an  hour.  It  is  also 
highly  susceptible  to  chemical  agents.  One  per  cent,  carbolic  acid, 
1 :  3,000,000  corrosive  sublimate  and  feebly  acid  solutions  kill  it  within 
a  few  minutes.  According  to  Harding  one  part  of  chlorin  to  one  mil- 
lion parts  of  water  destroys  the  bacillus  within  fifteen  minutes.  In 
distilled  water  it  soon  dies  but  in  ordinary  drinking-water  or  tank- 
water,  such  as  is  used  in  India,  it  may  retain  its  vitality  and  virulence 
for  weeks  and  even  months.  According  to  Hankin  the  organism  soon 


60  CHOLERA 

dies  in  the  water  of  the  Ganges,  which  is  feebly  acid.  How  quickly 
it  dies  in  stools  depends  on  many  conditions  such  as  dampness  and  light. 

No  lower  animal,  however  intimate  the  contact  with  infected  men 
may  be,  is  known  to  develop  cholera.  This  disease  seems  to  be,  at 
least  under  natural  conditions,  confined  exclusively  to  the  human 
species.  Furthermore,  no  one  has  succeeded  in  inducing  a  true  cholera 
in  an  animal  by  inoculation.  However,  some  of  the  attempts  to  accom- 
plish this  purpose  have  been  partially  successful  and  are  of  sufficient 
interest  to  justify  brief  review.  Filter  paper  impregnated  with  cholera 
cultures  fed  to  mice  induces  diarrhea,  but  filter  paper  alone  has  the 
same  effect.  Large  quantities  of  cholera  cultures  fed  to  pigs  cause 
death,  but  cultures  of  many  other  bacteria  produce  like  results. 

Nikali  and  Rietsch  opened  the  abdominal  cavities  of  guinea-pigs, 
tied  the  bile  duct  in  order  to  exclude  the  bactericidal  action  of  this 
fluid,  and  injected  cholera  cultures  into  the  duodenum.  In  the  intes- 
tines of  the  recovered  animals  the  cholera  bacilli  multiplied  and  the 
epithelial  lining  of  the  intestines  was  found  altered.  Other  bacteria 
behave  in  a  similar  manner.  Koch  neutralized  the  stomach  contents 
with  soda  and  then  introduced  cholera  culture  into  this  organ  through 
a  tube.  At  the  same  time  the  animals  were  stupefied  with  opium  from 
which  they  soon  recovered,  but  the  next  day  became  ill  and  died  on 
the  second  or  third  day  in  collapse.  After  death  the  intestine  was 
found  to  contain  a  colorless  fluid  consisting  of  a  pure  culture  of  the 
comma  bacillus.  Like  results  may  be  secured  with  other  vibrios. 
Indeed,  Metschnikoff  did  better  in  his  experiments  on  rabbits  with 
the  Vibrio  Maszanah  which  is  known  to  be  quite  different  from  Koch's 
comma  bacillus.  He  polluted  the  teats  of  a  mother  rabbit  with  this 
culture  and  found  that  at  least  half  of  the  nursing  young  died  of  a 
choleraic  diarrhea.  Moreover,  when  the  sick  young  rabbits  were  placed 
in  a  cage  with  healthy  fellows  from  another  litter,  many  of  the  latter 
became  infected.  Thomas  injected  cholera  cultures  into  the  ear  veins 
of  rabbits.  After  a  few  days  the  animals  died,  and  inflammatory 
changes  were  found  in  the  walls  of  the  intestines  and  cholera  bacilli 
in  the  intestinal  content. 

Many  bacteria  when  injected  intravenously  find  their  way  into 
the  intestine  and  may  induce  the  same  changes  in  the  intestinal  walls. 
Cholera  cultures  injected  into  the  abdominal  cavities  of  guinea-pigs 


CHOLERA  61 

cause  a  fatal  peritonitis.  Many  saprophytic  organisms  will  act  in  the 
same  way  and  quite  as  promptly.  It  is  safe  to  say  that  all  attempts 
to  induce  genuine  and  distinctive  Asiatic  cholera  in  the  lower  animals, 
made  up  to  the  present  time,  have  failed,  and  that  we  know  no  animal 
susceptible  to  this  disease  under  either  natural  or  experimental  con- 
ditions. To  man  alone  belongs  the  function  of  serving  as  host,  pre- 
server and  distributor  of  the  comma  bacillus.  Without  man  to  supply 
warmth,  shelter,  food  and  transportation,  the  cholera  bacillus  would 
soon  disappear  from  the  face  of  the  earth. 

Every  man  who  goes  into  battle  is  not  killed;  likewise  not  every 
man  who  swallows  the  cholera  bacillus  becomes  infected  and  of  the 
infected  all  do  not  die.  The  cholera  bacillus  is  highly  susceptible  to 
acids,  and  the  acidity  of  the  stomach  is  a  protective  agency.  But  the 
acidity  of  the  stomach  is  widely  variable  among  people  and  scarcely 
less  so  in  the  individual  from  time  to  time.  Infected  drink,  taken  when 
the  stomach  is  empty  and  non-acid,  is  likely  to  carry  its  infection  on 
into  the  alkaline  intestinal  content.  Bacilli  protected  by  masses  of 
food,  difficult  of  digestion,  may  also  pass  through.  In  the  midst  of 
cholera  epidemics,  many  harbor  the  bacillus  and  distribute  it  in  their 
stools  without  being  at  all  affected  by  it  Others  are  only  slightly  ill 
and  there  is  every  degree  of  gravity  up  to  those  in  which  the  disease 
is  fatal  within  a  few  hours. 

In  typical  cases  of  cholera  the  bacillus  does  not  find  its  way  through 
the  intestinal  walls.  It  multiplies  so  abundantly  in  the  intestinal  con- 
tent that  it  starves  out  all  other  bacteria  and  after  death  there  is  a 
pure  culture  in  the  intestine.  It  not  only  grows  abundantly,  but  its 
cells  speedily  die  and  in  doing  so  the  poison  contained  in  their  struc- 
ture is  liberated,  exerts  its  local  effects  on  the  intestinal  walls,  is 
absorbed  and  produces  the  symptoms  of  the  disease,  and  death.  In 
fact,  cholera  as  an  infection  is  limited  to  the  alimentary  canal;  as  an 
intoxication  it  kills. 

In  acute  cholera  the  bacillus  is  found  only  in  the  intestine  and  gall- 
bladder after  death.  All  other  organs  and  tissues  are  sterile.  The 
intestine  is  converted  into  a  great  culture  flask  from  which  the  chemi- 
cal poison,  elaborated  by  the  bacterial  growth,  diffuses  into  the  blood, 
while  the  water  from  the  blood  diffuses  into  the  flask.  This  results 
in  the  condensation  of  the  circulating  blood,  the  drying  out  of  the 


62  CHOLERA 

tissues,  the  suppression  of  urine,  perspiration,  saliva  and  even  of  the 
tears.  The  cholera  poison,  irritating  the  intestinal  wall,  increases 
peristalsis  until  it  becomes  most  painful  and  leads  to  the  ejection  of 
large  volumes  of  rice-water  stools.  The  constant  nausea  and  vomiting 
render  even  drinking  quite  impossible.  Through  mouth  and  anus  the 
culture  flask  is  discharged  while  it  is  constantly  replenished  by  the 
withdrawal  of  water  from  the  blood  and  tissue.  In  the  acute  form, 
a  few  hours  suffice  to  dry  out  the  tissues  so  thoroughly  that  death 
results. 

Several  cases  of  laboratory  infection  with  the  cholera  bacillus  have 
been  reported.  The  first  of  these  occurred  in  Koch's  laboratory  in 
1884.  A  careless  worker  infected  himself.  Dr.  Oergel  of  Hamburg 
died  from  accidental  infection  with  the  cholera  bacillus.  Some  half- 
dozen  additional  laboratory  infections  have  been  reported.  Besides 
these  accidental  infections,  several  have  intentionally  swallowed  cul- 
tures. The  most  notable  instance  of  this  kind  were  the  Munich  pro- 
fessors, Pettenkoffer  and  Emerich.  They  alkalized  their  stomachs  and 
then  drank  the  dilute  cultures.  The  former  suffered  only  a  severe 
diarrhea,  but  the  other  passed  into  the  algid  stage  with  suppression 
of  urine  and  barely  escaped  with  his  life.  A  similar  instance  occurred 
in  Paris  under  the  observation  of  Metschnikoff.  It  has  been  observed 
in  these  cases  that  the  period  of  incubation  is  short,  from  twenty-four 
to  forty-eight  hours. 

The  cholera  poison,  on  which  much  work,  ending  in  diverse  and 
even  contradictory  conclusions,  has  been  done,  is  probably  the  protein 
poison  found  in  all  proteins.  Ordinarily  this  poison  is  without  effect 
when  given  by  mouth  on  account  of  the  slowness  with  which  it  passes 
the  intestinal  wall,  but  with  the  lumen  of  the  intestine  filled  with  an 
abundant  cholera  culture,  the  walls  are  so  injured  that  the  poison  is 
rapidly  absorbed.  The  cholera  poison  is  not  more  active  than  that 
obtainable  from  other  bacteria,  both  pathogenic  and  non-pathogenic, 
also  from  other  proteins  both  vegetable  and  animal. 

Sources  of  Infection. — Every  case  of  cholera  means  that  some  one 
has  swallowed  bacilli  which  have  come  from  the  stools  of  some  one 
else.  The  route  may  have  been  quite  short  and  direct  or  may  have 
been  long  and  circuitous.  The  bacilli  bred  in  the  intestine  of  one  indi- 


CHOLERA  63 

vidual  may  find  their  way  into  the  mouth  of  another,  or  many  gen- 
erations of  bacilli  may  lie  between  the  two  subjects.  In  all  instances, 
the  connection  is  sure  and  certain.  This  disease  spreads  in  no  other 
way.  The  only  infected  discharges  from  the  cholera  patient  are  those 
that  come  from  the  alimentary  canal.  The  vomited  matter  may  con- 
tain virulent  bacilli  but  this  is  rarely  the  case  on  account  of  the  great 
susceptibility  of  the  organism  to  acid  solutions.  Practically  the  only 
infectious  discharge  is  the  stool.  Among  filthy  people  the  stool  may 
go  quite  directly  to  the  mouth  by  the  hands.  Mothers  often  infect 
their  children  in  this  way  and  sometimes  it  is  transferred  from  child 
to  parent. 

This  contact  infection  is  illustrated  in  the  voyage  of  the  Carlo  R. 
which  sailed  from  Naples,  Aug.  1,  1893,  for  Brazil,  with  1,472  steer- 
age passengers.  The  ship's  water  was  not  infected.  On  the  outward 
trip  cholera  appeared.  On  reaching  South  America  the  vessel  was 
not  permitted  to  dock  and  was  compelled  to  return.  The  double 
voyage  occupied  two  months  and  during  this  time  there  were  141 
deaths  among  the  steerage  passengers.  Scarcely  less  direct  is  the 
transference  from  soiled  clothing  or  bedding  or  when  the  infected 
stools  are  deposited  on  fruits  and  plants  which  are  subsequently  eaten. 
The  less  cleanly  people  are,  the  more  liable  to  harbor  this  disease. 

Before  the  discovery  of  the  bacillus,  Pettenkoffer  had  observed 
that,  in  its  European  visitations,  this  infection  spared  certain  localities. 
These  were  relatively  clean  places,  such  as  would  not  afford  oppor- 
tunity for  contact  infection.  The  great  outbreaks,  such  as  that  at 
Hamburg  in  1892,  are  due  to  infection  of  the  general  water-supply. 
At  that  time  Hamburg  used  the  unfiltered  water  from  the  Elbe.  At 
first  there  were  a  few  cases  among  those  employed  about  the  wharves. 
Finally  the  pollution  extended  up  the  river  and  reached  the  city 
water-supply.  The  first  case  was  recognized  early  in  August  and  the 
explosion  came  on  the  20th  of  the  same  month  and  by  the  31st  the 
number  of  new  cases  per  day  reached  one  thousand.  Hamburg  and 
Altoona  are  one  city,  but  separated  administratively.  On  one  side  of 
the  street  the  houses  are  in  Hamburg  and  on  the  other  in  Altoona. 
The  latter  had  a  separate  and  uninfected  water-supply  and  was  free 
from  the  disease  except  among  those  who  drank  from  the  Hamburg 
water. 


64  CHOLERA 

Certain  cities  in  Italy,  notably  Naples  and  Genoa,  have  in  recent 
years  been  mildly  infected  and  the  disease  has  been  kept  alive  by 
contact  infection,  but  their  water-supplies  being  free  from  pollution, 
severe  outbreaks  have  not  developed.  Suspected  persons  and  their 
families  and  neighbors  should  be  tested  by  an  examination  of  their 
stools  and  kept  under  observation  so  long  as  these  contain  the  bacilli. 
A  convalescent  may  carry  the  organism  in  his  intestine  and  expel  it 
in  his  feces  for  sixty  days  after  recovery.  Many  who  do  not  develop 
the  disease  carry  the  bacilli  and  distribute  them  in  their  stools. 


CHAPTER    VIII 


TYPHOID    FEVER 

History. — In  his  writings  on  epidemics,  Hippocrates  (fifth  century 
B.  C.)  describes  certain  continued  fevers  with  moderate  disturbances 
of  the  bowels,  much  wasting  and  delirium,  lasting  sometimes  forty 
days,  and  recovering  rarely  by  crisis,  more  frequently  irregularly. 
These  can  hardly  be  other  than  cases  of  typhoid  fever.  Galen 
observed  similar  cases  and  described  them  under  the  names  "hemitri- 
taeus"  (used  by  Hippocrates)  and  "febris  semitertiana."  These 
names  were  used  for  centuries.  In  the  seventeenth  century  Spigelius 
writing  under  the  title  "De  Febre  Semitertiana"  reports  necropsies  in 
which  spots  and  sloughs  were  observed  in  the  intestine.  Similar 
lesions  were  found  and  reported  by  other  Italian  physicians.  Near 
the  middle  of  the  same  century  an  English  physician,  Willis,  made 
necropsies  and  observed  like  changes  in  the  intestine.  About  the 
same  time,  the  father  of  English  medicine,  Sydenham,  described  a 
fever  lasting  from  fourteen  to  thirty  days  with  a  tendency  to  diarrhea, 
delirium  and  epistaxis. 

In  the  eighteenth  century  many  contributions  to  the  knowledge 
of  this  disease  were  made.  Morgagni  described  the  intestinal  ulcers, 
perforations,  and  enlarged  mesenteric  glands  and  spleen.  Tissot  of 
Lausanne  gave  a  good  description  of  the  disease  as  did  Huxham  of 
England.  The  latter's  picture  is  sketched  in  the  following  words : 

The  patient  at  first  grows  listless  and  feels  slight  chills  and  sudors  with 
uncertain  flushes  of  heat  and  a  kind  of  weariness  all  over.  This  is  always 
attended  by  a  heaviness  and  dejection  of  spirit.  A  nausea  and  disrelish  of 
everything  soon  follow.  Though  a  kind  of  lucid  interval  of  several  hours  inter- 
venes, yet  the  symptoms  return  with  aggravation,  especially  towards  night ;  the 
head  grows  more  heavy,  the  heat  is  greater,  the  pulse  quicker;  a  great  torpor 
or  obtuse  pain  affects  the  head  and  is  commonly  succeeded  by  some  degree  of 
delirium.  In  this  condition  the  patient  often  continues  five  or  six  days,  seem- 
ing not  very  sick;  about  the  seventh  or  eighth  day  the  giddiness,  pain  or  heavi- 
ness of  the  head  becomes  much  greater,  often  delirium  appears  with  universal 
tremors  and  muttering,  the  tongue  grows  often  very  dry,  often  very  thin  stools 


66  TYPHOID    FEVER 

are  discharged;  now,  nature  sinks  apace;  the  pulse  may  be  said  to  tremble  and 
flutter  rather  than  to  beat;  the  sick  man  becomes  quite  insensible;  and  the 
delirium  ends  in  a  profound  coma;  and  that  soon  in  an  eternal  sleep. 

Up  to  the  nineteenth  century  all  the  continued  fevers  with  delirium 
were  known  under  the  general  name  "typhus,"  which  means  smoky 
or  cloudy,  and  refers  to  the  mental  state.  Early  in  the  seventeenth 
century  some  of  the  more  observant  physicians  began  to  suspect  that 
two  quite  distinct  diseases  were  included  under  the  diagnosis  of 
typhus  and  on  this  point  there  grew  up  a  discussion  which  continued 
for  two  hundred  years.  In  order  to  gain  knowledge  to  settle  this 
question,  necropsies  were  frequently  resorted  to  and  most  minute  and 
exact  studies  of  the  lesions  were  made.  In  a  medical  way  the  dispute 
became  partially  at  least  an  international  one.  French  physicians,  led 
especially  by  Bretonneau  of  Tours,  held  that  in  their  necropsies  they 
found,  quite  usually,  lesions,  inflammatory  and  ulcerative,  in  the  ileum, 
while  British  physicians  for  the  most  part  failed  to  find  such  changes. 

The  great  clinicians  of  Paris  in  the  early  part  of  the  nineteenth 
century  were  Trousseau  and  Louis  and  these  were  earnest  in  present- 
ing their  views.  At  that  time  many  of  the  brighter  young  medical  men 
of  this  country  went  to  Paris  to  continue  their  studies.  There  they 
heard  the  lectures  and  saw  the  necropsies.  Stopping  in  Great  Britain 
in  their  visits  to  and  from  Paris,  they  heard  lectures  and  saw  necrop- 
sies. In  France  ulcers  were  found  in  the  intestines;  in  England  they 
were  not.  In  this  country  some  necropsies  revealed  intestinal  lesions 
while  others  did  not.  It  soon  became  evident  that  there  were  two 
distinct  diseases,  differing  not  only  in  the  lesions  found  after  death  but 
in  onset,  progress,  and  in  other  respects.  The  old  name,  typhus,  was 
retained  for  the  form  without  intestinal  lesions  and  the  new  term 
"typhoid"  given  to  that  with  such  lesions.  Louis  selected  the  new 
name,  and  in  giving  it  he  said:  "I  have  long  searched  for  a  word 
to  express  the  anatomical  character  of  this  disease  which  would  not 
be  disagreeable  to  the  ear,  and  having  failed  to  find  such  an  one,  I  have 
adopted  the  expression  'affection  typhoide/  as  being  at  least  free  from 
inconveniences."  Bretonneau  had  used  the  designation  "dothin- 
enterie"  meaning  pustule  in  the  intestine.  The  word  "typhoid"  is 
unfortunate  and  not  so  good  as  the  English  designation  "Enteric 


TYPHOID    FEVER  67 

fever."  The  Germans  know  it  as  "Abdominal  typhus."  Gerhard  of 
Philadelphia  is  generally  given  the  credit  of  finally  settling  the  dispute 
concerning  the  duality  of  the  old  typhus.  Valliex  wrote  in  1839: 
"Gerhard  established  for  the  first  time  the  very  important  fact  that 
there  can  exist,  and  that  there  do  exist,  at  the  same  time  in  the  same 
country  two  diseases  that  may  be  clearly  distinguished  and  in  which 
one  can  predict  during  life  the  lesions  which  will  be  found  after  death. 
These  diseases  are  typhoid  fever  and  the  true  typhus." 

Early  in  our  civil  war,  medical  officers  reported  fevers  which  in 
their  opinion  differed  from  typhoid  fever  as  seen  in  the  north.  The 
first  board,  appointed  (1861)  to  investigate  this  matter,  reported  that 
"the  fever  prevalent  among  the  soldiers  was  bilious  remittent  fever, 
which,  not  having  been  controlled  in  its  primary  stage,  has  assumed 
that  adynamic  type  which  is  present  in  enteric  fever."  A  second  board 
was  convened  (1862)  for  the  purpose  of  revising  the  sick  report. 
Major  Woodward,  the  chief  of  this  board,  insisted  that  "the  prevailing 
fevers  of  the  army  of  the  Potomac  were  hybrid  forms,  resulting  from 
the  combined  influences  of  malarial  poisoning  and  of  the  causes  of 
typhoid  fever,"  and  he  insisted  that  they  should  be  reported  as  "typho- 
malarial  fever."  This  designation  became  official  July  1,  1862,  and 
from  that  time  to  June  30,  1866,  57,400  cases,  with  5,360  deaths, 
were  reported  under  this  name. 

While  Woodward's  designation  of  the  disease  was  adopted,  his 
understanding  of  its  nature  was  quite  generally  ignored.  He  believed 
it  to  be  a  hybrid  resulting  from  coincident  malarial  and  typhoid 
infections  while  the  greater  part  of  the  profession  understood  it  to 
be  a  severe  form  of  malarial  infection.  In  Woodward's  opinion  typho- 
malaria  was  quite  as  severe  and  fatal  as  typhoid,  because  it  was 
typhoid  in  one  already  infected  with  malaria  or  vice  versa.  He  also 
believed  that  a  trace  of  scurvy,  often  unrecognizable  until  typhoid 
infection  developed  rendered  the  latter  more  grave.  The  majority  of 
physicians  and  the  laity  regarded  typho-malaria  as  a  severe  malaria,  but 
much  less  grave  than  typhoid ;  the  new  term  took  a  part  of  the  sting  out 
of  the  diagnosis  of  typhoid  and  many  a  practitioner  in  the  kindness  of 
his  heart,  in  his  desire  to  spare  patients  and  friends,  found  the  com- 
pound word  a  welcome  subterfuge.  With  the  mobilization  of  troops  in 
the  war  with  Spain  (1898)  the  same  fever  spread  rapidly  through 


68  TYPHOID    FEVER 

the  camps,  small  and  large,  north  and  south  of  the  Mason  and  Dixon 
line,  and  was  recorded  on  sick  reports  under  a  multitude  of  names, 
chiefly  malaria,  but  often  typho-malaria  and  many  other  designations 
hitherto  and  subsequently  unused.  The  board  of  medical  officers 
appointed  to  investigate,  employing  scientific  methods  of  diagnosis, 
soon  showed  that  malaria  was  very  infrequent  and  that  more  than 
99  per  cent,  of  the  cases  were  typhoid.  Among  nearly  20,000  cases, 
12  of  coincident  malarial  and  typhoid  infection  were  found  and  even 
in  these  the  malarial  manifestations  were  suppressed  during  the  course 
of  the  typhoid.  A  man  already  malarial  is  not  immune  to  typhoid  or 
vice  versa,  but  even  in  coincident  infection  there  is  no  peculiar  or 
characteristic  symptom  complex.  It  follows  that  "typho-malaria"  in 
any  sense  is  a  misnomer  and  should  not  be  used. 

Malaria  is  not  the  only  infection  which  may  be  coincident  with 
typhoid.  Cases,  though  few  in  number,  have  been  reported  in  which 
typhoid  has  been  coincident  with  the  following :  Malta  fever,  recurrent 
fever,  anthrax,  Asiatic  cholera,  diphtheria,  miliary  tuberculosis,  scarlet 
fever,  and  both  amebic  and  bacterial  dysentery.  These  facts  simply 
show  that  the  above  mentioned  infections  establish  no  immunity  to 
typhoid  nor  does  this  disease  protect  the  individual  against  other  bac- 
terial invasions.  Of  more  importance  are  the  secondary  infections 
which  may  develop  in  typhoid.  The  intestinal  lesions  open  ports  of 
entry  especially  for  pus-producing  bacteria,  which  may  develop 
abscesses  in  various  parts  of  the  body,  and  these  are  slow  to  heal  and 
difficult  to  reach. 

The  Bacillus. — In  1880  Eberth  discovered  short,  motile  bacilli  in 
the  spleen  and  mesenteric  glands  of  those  dead  from  typhoid  fever. 
Four  years  later  Gaffky  isolated  this  organism  and  secured  pure  cul- 
tures. An  almost  endless  amount  of  research  has  been  devoted  to  the 
Bacillus  typhosus  with  the  hope  of  finding  easy  means  of  sure  recog- 
nition under  all  conditions.  There  is  an  extensive  group  of  bacilli 
with  the  typical  typhoid  at  one  extreme  and  the  typical  colon  bacillus 
at  the  other  and  with  many  intermediate  varieties.  It  is  easy  enough 
to  distinguish  the  extremes,  but  it  still  remains  quite  impossible  to 
locate  exactly  every  member  of  this  group.  The  colon  bacillus  is  a 
normal  dweller  in  the  intestinal  tract  and  causes  trouble  only  when  it 


'TYPHOID    FEVER  69 

finds  its  way  into  some  place  where  it  has  no  business.  Normal  feces 
contain  colon  bacilli  in  great  numbers. 

When  the  typhoid  bacillus  finds  its  way  into  man's  intestinal  tract 
it  is  likely  to  develop  typhoid  fever.  The  stool  of  the  typhoid  victim 
is  laden  with  the  Bacillus  typhosus.  Between  the  extremes  of  the 
typho-colon  group,  there  are  two  varieties  of  the  B.  typhosus,  Para- 
typhus  A  and  B,  B.  enteritidis,  mouse  typhoid,  dysentery  bacilli  and  B. 
fecalis  alcaligenes.  A  typical  typhoid  bacillus  is  highly  motile;  it 
does  not  coagulate  milk ;  it  does  not  redden  litmus  milk ;  it  forms  blue 
colonies  on  plates  of  gelatine  colored  with  litmus;  when  grown  in 
whey  colored  with  litmus  it  produces  only  a  slight  cloudiness  and  at 
most  only  slightly  reddens  the  medium;  when  grown  in  fermentation 
tubes  in  a  solution  containing  grape  sugar  it  develops  no  gas;  when 
grown  in  agar  colored  with  neutral  red  it  does  not  change  the  color 
or  develop  any  gas;  when  grown  in  peptone  solutions  or  bouillon  it 
does  not  develop  indol.  A  typical  colon  bacillus  is  non-motile ;  it  does 
coagulate  milk ;  it  reddens  litmus  milk ;  it  forms  red  colonies  on  plates 
of  gelatine  colored  with  litmus;  when  grown  in  whey  colored  with 
litmus,  it  produces  a  marked  cloudiness  and  deeply  reddens  the 
medium;  when  grown  in  fermentation  tubes  in  solutions  of  grape 
sugar,  it  develops  gas  abundantly;  when  grown  in  agar  colored  with 
neutral  red  it  does  develop  gas  and  changes  the  color;  when  grown 
in  peptone  solution  or  bouillon  it  develops  indol.  It  will  be  seen  from 
these  facts  that  it  is  easy  to  distinguish  between  a  typical  typhoid  and 
a  typical  colon  bacillus,  but  there  are  varieties  of  each  which  may 
contradict  any  one  of  these  statements,  while  the  intermediate  organ- 
isms differ  from  one  another  and  in  their  own  varieties.  It  follows 
that  only  an  expert  in  this  line  is  fitted  to  locate  exactly  the  members 
of  this  large  group  of  organisms.  However,  with  proper  training  one 
becomes  quite  expert  and  the  identification  of  typhoid  bacilli  in  the 
stools  and  urine  of  suspected  cases  becomes  less  difficult  than  one 
would  suppose  from  the  above  statements. 

The  recognition  of  this  organism  in  drinking  water  remains  so  diffi- 
cult in  spite  of  all  the  work  that  has  been  done  that  it  is  seldom 
attempted  and  the  fitness  of  a  water  for  drinking  purposes  is  deter- 
mined by  the  number  of  colon  bacilli  in  a  given  volume  of  the  water. 
This  is  easily  done  by  counting  the  number  of  red  colonies  which 


70  TYPHOID    FEVER 

develop  on  litmus  gelatine  plates  or  on  gelatine  containing  some 
other  color  affected  by  the  colon  bacillus  in  a  similar  manner.  The 
number  of  red  colonies  developing  on  such  plates  is  taken  as  an  indi- 
cation of  the  extent  to  which  the  water  carries  fecal  contamination. 
If  fecal  matter  from  healthy  people  finds  its  way  into  the  water  that 
from  those  infected  with  the  typhoid  bacillus  may,  and  the  only  safe 
procedure  is  to  condemn  all  waters  bearing  fecal  matter.  This  does 
not  mean  that  the  colon  bacillus  in  any  of  its  varieties  will  cause 
typhoid  fever. 

Nothing  like  typhoid  exists  so  far  as  we  know  in  any  of  the  lower 
animals.  Moreover,  with  the  possible  exceptions  to  follow,  all 
attempts  to  induce  a  chronic  fever  with  the  typhoid  lesions  in  animals 
by  inoculation  with  the  specific  bacillus  have  failed.  Injected  in  large 
enough  doses  it  kills,  but  without  infection.  The  dead  bacillus  does 
the  same  thing.  This  shows  that  the  cellular  substance  contains  a  poi- 
son, but  this  is  true  of  all  bacteria,  both  pathogenic  and  non-pathogenic. 
Grunbaum  claims  to  have  developed  typhoid  fever  in  a  chimpanzee 
and  Weinberg  reports  positive  results  with  apes  infected  with  certain 
intestinal  parasites,  which  inflict  on  the  mucous  membrane  wounds 
through  which  the  bacillus  find  entrance.  While  our  domestic  animals 
do  not  become  infected  with  this  bacillus,  they  may  bear  it  from  place 
to  place  on  their  bodies  or  distribute  it  in  their  excretions.  Several 
cases  of  accidental  laboratory  infection  and  a  few  acquired  inten- 
tionally have  occurred.  These  demonstrate  the  pathogenicity  of  the 
bacillus  for  man. 

Sources  of  Infection. — It  is  true  of  typhoid  fever,  as  it  is  of 
Asiatic  cholera,  that  every  case  of  infection  is  due  to  the  transference 
of  the  fecal  matter  of  the  infected  either  by  a  short  or  a  long  circuit, 
to  the  alimentary  canal  of  another,  There  is,  however,  this  important 
difference ;  cholera  is  widely  disseminated  only  at  certain  times  and  in 
certain  places,  while  typhoid  is  well-nigh  ubiquitous.  Up  to  the  pres- 
ent time  there  is  no  part  of  the  world  absolutely  free  from  this  disease 
for  any  great  length  of  time.  In  one  sense  typhoid  is  a  filth  disease 
inasmuch  as  it  is  scattered  through  the  excretions  of  the  human  body, 
especially  in  the  urine  and  feces.  No  wonder  that  it  was  thought  that 
typhoid  may  originate  de  novo.  Now,  we  know  that  this  is  not  true, 


TYPHOID    FEVER  71 

but  until  the  discovery  of  the  causal  agent  this  truth  was  difficult  of 
demonstration. 

It  follows  from  what  has  been  said  that  the  prevalence  of  typhoid 
in  any  community  is  largely  determined  by  the  personal  cleanliness 
of  the  inhabitants  and  largely  by  the  method  of  disposing  of  human 
excreta.  In  the  past  typhoid  has  been  the  most  destructive  disease  in 
armies,  miners'  camps,  exploring  parties  and  wherever  the  disposal 
of  fecal  matter  has  been  primitive  and  imperfect.  The  dissemination 
of  this  disease  among  our  soldiers  in  1898  was  thoroughly  investigated, 
and  some  of  the  conclusions  may  be  not  only  of  interest  but  of  value  to 
civilians. 

During  the  Spanish  war  of  1898  every  regiment  constituting  the 
first,  second,  third,  fourth,  fifth  and  seventh  army  corps  developed 
typhoid.  This  includes  all  the  soldiers  assembled  in  that  war  except 
those  who  went  to  the  Philippines  and  consequently  were  not  investi- 
gated by  the  board.  More  than  90  per  cent,  of  the  volunteer  regiments 
developed  typhoid  within  eight  weeks  after  going  into  camp.  The 
disease  developed  in  certain  of  the  regular  regiments  within  from 
three  to  five  weeks  after  going  into  camp.  These  facts  negative  an  old 
claim  that  sudden  change  from  civilian  to  military  life  favors  the 
development  of  this  disease.  The  disease  became  epidemic  in  small  and 
large  camps,  in  those  in  the  north  as  well  as  in  those  in  the  south. 
It  had  been  held  that  simply  bringing  large  numbers  of  men  together 
was  enough  in  and  of  itself  to  cause  a  typhoid  epidemic.  Some  had 
argued  that  change  of  climate  alone  caused  the  disease. 

At  that  time  typhoid  was  so  widely  and  abundantly  distributed  in 
this  country,  the  chances  were  that  whenever  and  wherever  one  thou- 
sand or  more  men  should  be  brought  together,  an  average  of  four  in 
this  number  would  reach  the  camp  already  infected.  Those  who  came 
with  the  infection  would  scatter  the  seeds  before  the  disease  in  them 
would  be  recognized.  The  number  of  cases  in  the  different  camps 
varied  directly  with  the  methods  of  disposing  of  the  excretions.  The 
disease  was  disseminated  by  contact,  by  flies  and  by  water.  Contact 
infection  was  the  most  important  factor.  The  grounds  were  covered 
in  some  places  with  feces.  The  men  tracked  this  infected  matter  into 
their  tents,  soiled  the  floors,  blankets,  clothing,  and  tents.  Men  were 
detailed  to  act  as  orderlies  at  the  hospitals  where  they  handled  bed 


72  TYPHOID    FEVER 

pans  and  otherwise  polluted  their  clothing  and  person,  and  then 
returned  to  their  mess  tents  and  handled  food  for  themselves  and 
passed  it  to  their  neighbors  without  even  washing  their  hands.  It 
was  estimated  that  in  some  regiments  at  least  60  per  cent,  of  the  cases 
were  contracted  through  lack  of  personal  cleanliness  and  the  conse- 
quent pollution  of  clothing,  bedding,  tentage,  food,  etc.  Flies  served 
as  carriers  of  the  infection.  They  swarmed  over  infected  matter  in 
the  latrines  and  then  visited  and  fed  on  the  food  prepared  for  the 
soldiers  at  the  mess  tents.  In  some  instances  when  lime  had  recently 
been  spread  over  the  fecal  matter  in  the  latrines,  flies  with  their  feet 
whitened  with  lime  were  seen  on  the  food.  Flies  carry  the  bacilli  on 
their  bodies  mechanically  and  pollute  what  they  subsequently  touch  and 
they  eat  infected  matter,  swallowing  the  bacilli,  which  they  subse- 
quently deposit  with  their  own  excretions.  In  some  camps  the  water- 
supply  was  contaminated  by  the  natural  drainage  from  the  infected 
earth. 

At  Jacksonville,  Fla.,  it  was  probable  that  infection  through  inhala- 
tion was  a  minor  factor  in  the  spread  of  the  disease.  Change  of  loca- 
tion did  not  rid  the  soldiers  of  the  infection,  because  they  carried  it 
with  them,  in  their  intestines,  on  their  hands,  in  their  clothing,  blankets 
and  tentage.  They  even  transported  the  infection  with  them  to  Cuba 
and  Porto  Rico.  These  are  fair  samples  of  the  dissemination  of 
typhoid  not  only  in  military  but  in  civil  life,  for  the  difference  is  only 
one  of  degree.  Every  village  is  a  small  camp  and  every  city  a  larger 
one.  Typhoid  in  the  past  was  more  prevalent  in  military  than  in  civil 
life  because  in  our  more  permanent  homes  we  dispose  of  our  excreta 
more  effectively.  Had  we  not  learned  to  do  so,  urban  life  would  have 
remained  impossible  as  it  once  was. 

It  must  not  be  inferred  from  the  above  brief  account  of  typhoid 
in  1898  that  our  soldiers  were  less  cleanly  or  more  ignorant  than  those 
of  other  nations.  When  the  Franco-German  war  began,  every  corps  of 
the  German  army  was  infected  with  typhoid  and  the  second  division  of 
the  eleventh  corps  was  at  that  time  suffering  from  a  marked  epidemic 
of  this  disease.  The  infection  was  not  confined  to  the  Prussians,  but 
extended  to  every  contingent  of  the  German  army.  The  seeds  of  the 
disease  carried  with  them  rapidly  bore  fruit,  especially  among  the 
troops  besieging  Metz  and  later  at  Paris.  Within  less  than  two  months 


TYPHOID    FEVER  73 

after  war  was  proclaimed  typhoid  had  extended  so  extensively  among 
certain  divisions  of  the  German  troops,  notably  in  the  eleventh  corps 
of  the  Prussian  soldiers  and  in  the  Wurtemberg  division,  that  more 
than  15  per  cent,  of  these  commands  were  sick  of  this  disease.  The 
total  number  of  cases  among  the  under  officers  and  men  in  the  Ger- 
man army  during  the  Franco-German  war  amounted  to  73,396,  which 
was  equivalent  to  9.31  per  cent,  of  the  average  strength.  The  invasion 
of  France  began  about  the  middle  of  July,  1870.  During  the  second 
half  of  this  month  the  total  number  of  cases  in  the  German  army  was 
345,  less  than  the  average  for  preceding  years  of  peace.  In  August 
the  number  perceptibly  increased,  amounting  to  2.6  per  thousand,  but 
not  enough  to  cause  apprehension,  and  up  to  September  it  could  not 
be  said  that  there  was  an  unusual  prevalence  of  the  disease.  Early 
in  this  month  there  was  an  explosive  outbreak  and  the  cases  ran  up 
to  12,463,  which  was  equivalent  to  15.3  per  thousand.  In  October 
there  were  17,253  new  cases.  In  this  month  the  epidemic  reached  its 
climax  and  fell  slowly. 

Typhoid  may  be  transported  by  an  army  into  regions  practically 
uninhabited.  This  is  illustrated  by  the  Afghan  war  of  1878-80.  Some 
of  the  sites  occupied  by  English  soldiers  were  never  before  peopled. 
It  is  not  at  all  likely  that  the  waters  of  the  mountain  streams  were 
specifically  contaminated  with  the  typhoid  bacillus;  nor  was  it  likely 
that  the  virgin  soil  covered  by  these  encampments  was  infected,  except 
as  it  became  so  by  occupation,  and  yet  typhoid  developed  at  nearly 
every  station  occupied  by  the  English  troops.  Only  one  explanation  is 
possible.  It  is  known  that  the  English  troops  drawn  from  various 
parts  of  India  were  widely  infected  with  typhoid  when  the  invasion  of 
Afghanistan  was  begun.  A  similar  experience  is  furnished  by  the  his- 
tory of  French  expeditions  in  Northern  Africa.  In  the  Oran  cam- 
paign, in  1885,  French  commands  encamped  in  desert  stations  never 
before  occupied,  and  in  these  typhoid  not  only  appeared,  but  devel- 
oped epidemic  proportions.  In  the  English  expedition  to  Suakin  in 
1885  every  precaution  was  taken  to  supply  the  troops  with  pure  water. 
In  fact  the  drinking  water  was  distilled.  Notwithstanding,  typhoid 
developed  extensively.  The  east  Surrey  regiment  joined  the  expedi- 
tion already  infected  and  it  is  more  than  likely  that  these  men  infected 
the  latrines  and  the  disease  was  spread  by  contact  and  by  flies.  In 


74  TYPHOID    FEVER 

the  expedition  for  the  relief  of  Chitral  in  1895  typhoid  infection  was 
carried  by  the  soldiers,  and  when  they  encamped  at  Kahr  an  epi- 
demic developed.  In  the  invasion  of  Egypt  infected  regiments  were 
drawn  from  Mediterranean  stations.  On  the  disembarkment  at 
Ismalia  occasional  cases  began  to  appear  and  continued  to  do  so  until 
a  serious  epidemic  manifested  itself  in  the  permanent  camp  at  Cairo. 
In  the  South  African  war  the  English  failed  to  profit  by  the  lesson 
for  which  all  nations  had  paid  so  dearly.  The  restriction  of  typhoid 
in  armies  was  first  successfully  practiced  in  the  Russo-Japanese  war 
by  both  parties  and  this  was  the  first  great  war  in  which  the  victims 
of  typhoid  did  not  greatly  add  to  the  death  lists.  Now,  with  our 
knowledge  of  sanitation,  aided  by  the  protection  afforded  by  vaccina- 
tion, typhoid  in  both  military  and  civil  life  should  recede  rapidly  and 
soon  be  known  only  in  the  records  of  the  past. 

The  typhoid  bacillus  is  eliminated  from  the  infected  person  chiefly 
in  the  stools  and  urine.  Vomited  matter,  the  saliva  and  the  discharges 
from  posttyphoidal  abscesses  may  contain  the  virus,  but  compared  with 
the  stools  and  the  urine  these  are  of  minor  importance.  The  stools 
of  every  person  infected  with  this  disease  contain  the  bacilli,  but  in 
widely  varying  amounts,  from  a  few,  difficult  of  recognition  on  account 
of  the  great  numbers  and  rapid  growth  of  other  bacteria,  up  to  a  pure 
culture.  As  a  rule,  typhoid  bacilli  are  most  numerous  in  the  stools 
during  the  third  week  of  the  disease,  at  a  time  when  the  intestinal 
ulcers  are  sloughing.  The  stools  of  all  suffering  from  this  disease 
should  be  thoroughly  disinfected.  However,  the  bacilli  may  be  present 
in  the  stools  both  before  the  disease  is  recognized  clinically,  and  long 
after  clinical  recovery.  In  many  instances  the  stools  continue  to  be 
infected  for  from  six  to  eight  weeks  after  the  subsidence  of  the  fever. 
In  a  few  instances  the  individual  becomes  a  constant  and  chronic  car- 
rier of  the  infection  and  may  remain  so  for  years.  Moreover,  every- 
one who  harbors  this  organism  does  not  develop  the  disease.  Any  one 
of  these  classes,  the  convalescent,  the  carrier  and  the  apparently  well 
man,  may  infect  wide  areas  and  diverse  places.  The  only  hope  of 
complete  protection  lies  in  provision  for  the  disposal  of  the  excreta 
of  all  men  in  such  manner  that  they  cannot  find  their  way,  directly  or 
indirectly,  by  short  or  long  circuit,  into  the  alimentary  canal  of  others. 


TYPHOID    FEVER  75 

The  urine  in  about  30  per  cent,  of  cases  of  typhoid  is  infected  with  the 
bacillus  and  carriers  may  distribute  the  infection  through  this  excretion. 

Contact  infection  is  the  most  common  mode  in  the  distribution  of 
typhoid.  Different  students  of  epidemiology  in  widely  distant  lands 
agree  in  this  and  even  go  so  far  as  to  place  practically  the  same  esti- 
mate on  the  number  of  cases  originating  in  this  manner.  About  60 
per  cent,  of  all  cases  of  typhoid  are  believed  to  be  due  to  contact 
infection.  The  board  of  medical  officers  in  1898  placed  the  percentage 
of  contact  cases  at  62.80,  while  Drigalski  gives  it  for  Germany  as 
64.7.  These  conclusions  seem  to  have  been  reached  quite  indepen- 
dently, inasmuch  as  the  German  makes  no  mention  of  the  American 
studies  which  were  conducted  nine  years  before  his.  Formerly,  it 
was  supposed  that  typhoid  is  mostly  water-borne  and  the  board  of 
officers  began  their  investigations  possessed  fully  of  this  view,  but  their 
studies  convinced  them  that  this  is  an  error  and  first  furnished  indis- 
putable evidence  that  contact  is  the  most  important  factor  in  the  dis- 
tribution of  typhoid.  Contact  is  both  direct  and  indirect.  The  board 
divided  the  cases  between  the  two  as  follows :  Direct,  35.01 ;  indirect, 
27.79  per  cent.  In  more  than  90  per  cent,  of  the  cases  due  to  direct 
contact  the  hands  bear  the  infection  directly  to  the  mouth.  Klinger 
found  this  to  be  true  in  1,315  out  of  1,397  cases.  This  certainly  should 
emphasize  the  importance  of  personal  cleanliness. 

In  indirect  contact  infection,  clothing,  bedding,  drinking  cups, 
dishes,  foods,  etc.,  may  serve  in  the  transport  of  the  infection  from 
one  person  to  another.  Soiled  clothing  may  retain  virulent  bacilli. 
Soiled  blankets  shipped  from  South  Africa  in  the  Boer  war  carried 
the  infection  to  those  who  used  them  in  England.  In  the  Spanish  war 
our  camps  were  not  rid  of  infection  until  the  clothing  of  the  soldiers, 
their  beddings  and  the  tents  were  disinfected.  Infected  fecal  matter 
deposited  on  oyster  beds  render  this  article  of  food  dangerous. 
Infected  employees  in  dairies  spread  the  infection  through  milk  and 
its  products.  Not  infrequently  cases  are  so  distributed  as  to  show  the 
route  of  the  milk  man.  Greens  and  salads,  fruits  and  berries  may 
become  bearers  of  typhoid  infection. 

Water  epidemics  are  explosive  in  outburst  and  are  characterized 
by  the  simultaneous  infection  of  a  large  number  of  those  who  con- 
sume the  water.  In  flowing  water  the  typhoid  bacillus  dies  out  in  from 


76  TYPHOID    FEVER 

five  to  ten  days.  In  still  water  it  may  continue  to  live  for  a  much 
longer  time.  In  dead  ends  of  water  pipes  it  may  linger  for  many 
days;  indeed,  the  statement  is  made  that  it  has  been  found  in  dead 
ends  months  after  the  infection  of  the  general  supply  has  disappeared. 
Of  course,  the  water  is  infected  with  the  excretions  of  man. 

Typhoid  infection  is  widely  distributed  by  boats  and  cars.  At 
present  there  is  no  attempt  to  disinfect  the  waste  from  the  water- 
closets  on  either  of  these  vehicles  of  transportation.  Some  years  ago 
when  on  account  of  a  break  in  the  locks  at  Sault  Ste.  Marie,  many 
downward-bound  boats  were  detained  above  the  intake  of  the  city's 
water-supply,  an  explosive  outbreak  of  typhoid  developed.  From  rail- 
road trains  fecal  matter  is  scattered  along  the  roadbed  and  sometimes 
this  is  specifically  infected.  This  filth  may  be  washed  into  water- 
supplies  or  it  may  be  scattered  in  dust  to  infect  workers  on  the  road 
and  even  travelers  on  trains.  The  prevalence  of  typhoid  fever  is 
not  a  credit  to  any  community  and  is  an  indication  that  filth  finds  its 
way  into  the  mouths  of  the  inhabitants. 

It  is  estimated  that,  taking  into  consideration  the  distribution  of 
typhoid  fever  over  a  large  area  and  for  a  long  time,  about  5  per  cent. 
of  it  is  due  to  the  infection  of  milk.  The  bacilli  multiply  rapidly  in 
milk  until  it  sours.  Whether  or  not  pasteurized  milk  may  contain  the 
living  bacillus  depends  on  the  temperature  used  in  the  process  and  the 
thoroughness  with  which  it  is  carried  out.  A  temperature  of  62  C. 
for  five  minutes  is  not  enough  to  insure  the  destruction  of  this  organ- 
ism in  milk.  This  is  the  temperature  at  which  this  process  was  for- 
merly generally  carried  out,  and  at  which  it  is  now  sometimes  done. 
In  an  improved  process  the  temperature  is  carried  to  85  C.,  which  is 
high  enough  to  destroy  this  virus  in  milk  in  one  minute.  In  butter 
this  bacillus  can  live  for  weeks. 

Attention  has  already  been  called  to  the  house  fly  as  a  distributor 
of  this  disease.  In  some  sections  of  this  country  the  crusade  against 
this  pest  has  not  been  pushed  with  sufficient  energy  and  it  is  still  in 
evidence  both  in  the  privy  vault  and  in  the  dining  room.  Ants  and 
other  insects  distribute  fecal  matter  deposited  on  the  earth  and  may 
carry  the  infection  to  plants  and  fruits. 


CHAPTER    IX 


ANTHRAX 

History. — This  disease  is  supposed  to  be  referred  to  in  the  book 
of  Exodus  (9:10),  the  reading  of  which  is  as  follows:  "And  it  became 
a  boil  breaking  forth  with  blains  upon  man  and  upon  beast." 

Homer's  acquaintance  with  anthrax  may  have  inspired  these  lines 
(Iliad,  B.  L): 

"And  first  the  beasts  assailed  he,  the  mule  and  ranging  hound, 
But  soon  at  man  his  firebolt  shot,  smiting  to  the  ground." 

The  pestilence  described  in  the  CEdipus  of  Seneca  is  regarded  by 
some  as  a  dramatic  description  of  an  anthrax  epidemic.  The  first 
victims  are  the  domestic  animals,  one  after  another,  until  men  and 
all  beasts  are  being  hopelessly  devoured  by  the  insatiable  anger  of 
the  gods: 

The  sluggish  ewes  first  felt  the  blight, 

.For  the  woolly  flock  the  rich  grass  cropped 

To  its  own  doom.     At  the  victim's  neck 

The  priest  stood  still,  in  act  to  strike; 

But  while  his  hand  still  poised  the  blow, 

Behold  the  bull  with  gilded  horns, 

Fell  heavily;  whereat  his  neck, 

Beneath  the  shock  of  his  huge  weight, 

Was  broken  and  asunder  yawned. 

No  blood  the  sacred  weapon  stained, 

But  from  the  wound  dark  gore  oozed  forth. 

The  steed  a  certain  languor  feels, 

And  stumbles  in  his  circling  course, 

While  from  his  downward  sinking  side 

His  rider  falls.    .    .    . 

The  abandoned  flocks  lie  in  the  fields ; 

The  bull  amid  his  dying  herd 

Is  pining;  and  the  shepherd  fails 

His  scanty  flock,  for  he  himself 

Mid  his  wasting  kine  is  perishing. 

The  stag  no  more  fears  the  ravenous  wolf; 


78  ANTHRAX 

No  longer  the  lion's  roar  is  heard ; 
The  shaggy  bear  has  lost  her  rage, 
And  the  lurking  serpent  his  deadly  sting; 
For  parched  and  dying  now  he  lies 
With  venom  dried. 

Another  classical  description  is  given  by  Ovid  (Metam.  vii).  Pliny 
(Hist.  Nat.  Lib.  xxvi)  says: 

We  find  it  stated  in  the  annals,  that  it  was  in  the  censorship  of  L.  Paulus 
and  Q.  Marcius  (164  A.  D.)  that  carbuncle  was  first  introduced  into  Italy,  a 
malady  which  till  then  had  confined  itself  to  the  province  of  Gallia  Narbonensis 
(now  Provence).  In  the  year  in  which  I  am  now  writing  these  lines  two  per- 
sons of  consular  rank  have  died  of  this  disease ;  Julius  Rufus  and  Q.  Lecanius 
Bassus;  the  former  in  consequence  of  an  incision  unskillfully  made  by  his 
medical  attendant,  the  latter  through  a  wound  upon  the  thumb  of  the  left  hand 
by  pricking  a  carbuncle  with  a  needle,  a  wound  so  small  originally  as  to  be 
hardly  perceptible. 

Arabian  physicians  described  anthrax  as  Persian  fever.  In  the 
ninth  and  tenth  centuries  the  disease  was  widely  disseminated  over 
Europe.  In  the  years  1375-76  it  is  reported  that  even  wild  animals 
died  of  anthrax.  According  to  Kircher  in  1617  most  of  the  domestic 
animals  and  60,000  people  died  of  this  disease.  It  continued  to  be 
widely  prevalent  in  Europe  down  to  the  time  of  scientific  medicine 
and  isolated  epidemics  still  occur.  In  the  sixties  of  the  last  century 
an  outbreak  in  Russia  was  investigated  by  a  German  commission  and 
reported  as  anthrax.  From  1864  to  1870  in  the  province  of  Novgorod 
more  than  65,000  domestic  animals  (horses,  cattle  and  sheep)  and 
528  people  succumbed  to  this  infection.  It  has  been  extensively 
disseminated  in  South  America,  especially  in  Brazil,  where  it  is  known 
as  "Garotilha."  It  is  well  established  in  Australia  where  it  has  inter- 
fered greatly  with  sheep  raising.  It  has  found  its  way  into  most  parts 
of  Asia  and  Africa.  In  our  own  country  it  has  appeared  only  as  local 
epidemics  among  cattle  and  isolated  cases  among  men,  known  as  wool- 
sorter's  disease  and  malignant  pustule.  Sobernheim  gave  the  total 
number  of  deaths  from  this  disease  among  cattle,  horses,  sheep  and 
goats  in  Germany  from  1900  to  1909  inclusive  as  55,410. 

Since  anthrax  is  the  most  typically  infectious  of  all  diseases,  and 
since  so  many  theories  have  been  evolved  concerning  it,  we  may  be 
pardoned  for  briefly  reviewing  the  literature.  As  early  as  1805 


ANTHRAX  79 

Kausch  wrote  a  monograph  on  this  disease  in  which  he  held  that  it  is 
due  to  paralysis  of  the  nerves  of  respiration;  but  he  offered  no 
explanation  of  the  paralysis.  Delafond  held  that  anthrax  has  its 
origin  in  the  influence  of  the  chemical  composition  of  the  soil  on  the 
food,  thus  inducing  pathologic  changes  from  malnutrition.  The  con- 
tagious nature  of  the  disease  was  clearly  established  in  1845  by 
Gerlach.  This  was  confirmed  by  the  studies  of  Heuzinger  and  was 
endorsed  by  Virchow  in  1855,  since  which  time  it  has  never  been 
questioned.  However,  as  early  as  1849  the  bacilli  had  been  seen  by 
Pollender.  Pollender  did  not  publish  his  observations  until  1855,  but 
he  states  that  they  were  made  in  the  fall  of  1849.  First,  he  examined 
the  blood  of  five  cows  dead  from  anthrax,  and  compared  this  with 
material  taken  from  the  spleen  of  a  healthy  animal.  The  examina- 
tions were  not  made  until  from  eighteen  to  twenty-four  hours  after 
death,  and  he  states  that  the  blood  was  stinking,  thus  indicating  that 
it  had  become  contaminated  with  putrefactive  organisms,  but  the 
description  which  he  gives  shows  that  he  actually  saw  anthrax  bacilli. 
He  used  a  crude  compound  microscope  made  by  Plossl,  and  he  gave 
his  attention  to  the  blood  corpuscles,  chyle  globules,  and  the  bacilli. 

His  description  of  the  micro-organisms  may  be  condensed  as  fol- 
lows: The  third  and  most  interesting  microscopic  bodies  seen  in 
anthrax  blood  are  innumerable  masses  of  rod-like,  solid,  opaque 
bodies,  the  length  of  which  varies  from  1/400  to  1/200  of  a  line,  and 
the  breadth  averages  1/3,000  of  a  line.  They  resemble  the  "vibrio 
bacillus"  or  "Vibrio  ambiguosus"  They  are  non-motile  and  neither 
water  nor  dilute  acids,  nor  strong  alkalies  have  any  effect  on  them, 
and  for  this  reason  he  concluded  that  they  must  be  regarded  as  vege- 
table organisms.  He  questioned  whether  they  existed  in  the  blood  of 
the  living  animal  or  resulted  from  putrefaction,  but  was  inclined  to 
believe  the  former,  and  thought  they  might  represent  the  infecting 
organism,  or  at  least  the  bearer  of  the  infection.  It  will  be  seen  that 
Pollender  presented  no  positive  proof  that  these  rod-like  bodies  had 
any  causal  relation  to  the  disease.  In  1856  Brauel  inoculated  sheep, 
horses  and  dogs  with  blood  taken  from  animals  sick  with  anthrax,  and 
in  this  way  demonstrated  that  the  disease  could  be  transmitted  to 
sheep  and  horses,  but  not  to  dogs.  He  found  sheep  highly  susceptible, 
horses  less  so,  and  dogs  quite  immune.  He  also  demonstrated  the 


80  ANTHRAX 

presence  of  the  bacilli  in  the  blood  of  sick  animals  before  death.  It  is 
interesting  to  note  that  he  fell  into  an  error  concerning  the  motility  of 
the  bacilli.  He  states  that  when  seen  in  fresh  blood  they  are  non- 
motile,  but  later  they  become  highly  motile.  This  was,  of  course,  due 
to  contamination.  It  should  be  noted  that  Brauel  also  made  examina- 
tion of  the  blood  of  various  domestic  animals  suffering  from  other 
diseases,  and  demonstrated  the  absence  of  the  bacillus  in  these. 

In  1863  Davaine  published  three  valuable  papers  on  anthrax.  In 
the  first  he  states  that  in  1850  Rayer  inoculated  sheep  with  the  blood 
of  others  dead  from  anthrax,  and  in  this  way  transmitted  the  disease. 
It  appears  that  Rayer  published  a  short  note  of  this  work  in  the 
Bulletin  de  la  Societe  de  Biologic  in  1850,  but  I  have  not  had  access 
to  this  publication.  Davaine's  own  work  was  of  the  greatest  value 
and  shows  great  skill  for  that  time.  Probably  the  most  important 
experiments  that  he  made  were  those  in  which  he  demonstrated  that 
the  blood  of  an  animal  sick  with  anthrax  is  not  capable  of  transmitting 
the  disease  to  others  unless  it  contains  the  bacillus.  It  may  be  of 
interest  to  describe  briefly  the  experiments  which  led  to  the  establish- 
ment of  this  fact.  Rabbit  A  was  inoculated  with  anthrax  blood. 
Forty-six  hours  later,  examination  showed  no  bacilli  in  the  blood  of 
Rabbit  A.  At  that  time  twelve  or  fifteen  drops  of  blood  were  taken 
from  the  ear  of  this  animal  and  injected  into  Rabbit  B.  Nine  hours 
later  the  blood  of  Rabbit  A  was  reexamined  and  found  to  contain  a 
large  number  of  bacilli.  This  blood  was  injected  subcutaneously  into 
Rabbit  C.  One  hour  later  Rabbit  A  died,  and  twenty  hours  later 
Rabbit  C  died,  while  Rabbit  B  remained  free  from  infection.  Space 
will  not  permit  us  to  follow  the  literature  of  anthrax  further.  Pasteur, 
DeBarry,  Koch  and  others  studied  the  morphology,  life  history,  and 
cultural  characteristics  of  the  bacillus,  and  in  this  way  founded  the 
science  of  bacteriology. 

The  Bacillus. — This  is  a  long  (4-10  microns),  slender  (1-1.3 
microns)  rod  with  rounded  ends.  A  drop  of  blood  from  the  spleen  of 
an  animal  dead  of  this  disease  discloses,  even  without  stain,  great 
numbers  of  these  bacteria.  They  are  non-motile  and  take  the  basic 
aniline  dyes  easily.  Often  many  bacilli  are  attached  end  to  end,  form- 
ing what  is  known  as  bamboo  rods.  These  are  quite  characteristic  but 


ANTHRAX  81 

are  not  seen  in  all  preparations.  Many  bacilli  show  capsules  which 
are  less  deeply  stained  and  the  contrast  is  quite  striking.  It  is  sup- 
posed that  this  capsule  protects  the  bacillus  against  the  destructive 
action  of  the  secretions  of  the  body  cells.  At  least,  bacilli  taken  from 
infected  animals  generally  show  the  capsules,  while  subcultures  seldom 
do.  It  has  been  found  that  cultures  grown  in  fluid  blood  serum  do 
show  the  capsule.  These  facts  indicate  that  the  capsule  results  from 
some  reaction  between  the  organism  and  blood.  It  will  continue  to 
live,  but  will  not  multiply  in  the  absence  of  air  and  consequently  must 
be  classed  as  an  aerobe.  It  grows  under  a  wide  range  of  temperature 
(15  to  43  C),  but  its  optimum  growth  is  at  or  near  the  temperature 
of  the  animal  body  (37  to  38  C.). 

It  grows  easily  on  all  the  ordinary  culture  media.  In  undis- 
turbed bouillon  it  does  not  produce  a  uniform  cloudiness,  but  appears 
in  floccules.  On  gelatine  plates  after  from  two  to  three  days  at  from 
18  to  20  C.  it  develops  characteristic  colonies.  Under  a  low  power 
these  are  seen  to  be  not  compact  as  is  the  case  with  most  bacterial 
colonies,  but  loosely  aggregated.  The  edges  are  not  smooth  and 
sharply  defined,  but  more  or  less  fringed.  These  are  known  as  medusa 
forms  and  the  fringe  is  due,  as  is  shown  under  a  higher  power,  to 
the  growth  of  the  rods  from  the  central  mass  into  the  surrounding 
medium.  It  forms  a  proteolytic  ferment  which  gradually  digests  or 
liquefies  the  gelatine  and  the  colonies  subside  into  the  craters  thus 
formed.  In  stick  gelatine  cultures  the  bacillus  grows  along  the  line 
and  branches  off  on  the  sides  forming  a  picture  which  has  been  vari- 
ously designated  as  a  brush  or  as  an  inverted  pine  tree;  very  slowly 
liquefaction  proceeds  from  the  surface  downward.  On  agar  plates  the 
colonies  are  much  like  those  on  gelatine,  with  the  exception  that  on 
the  former  spore  formation  may  be  observed.  Stick  cultures  on  agar 
are  much  like  those  on  gelatine,  with  no  liquefaction  and  a  spreading 
of  the  growth  over  the  surface  of  the  medium.  It  coagulates  milk 
and  then  digests  the  coagulum.  With  an  abundant  supply  of  oxygen 
digestion  may  proceed  so  quickly  that  coagula  are  not  seen. 

The  anthrax  bacillus  multiplies  by  transverse  fission,  but  when 
it  finds  the  conditions  of  life  unfavorable,  it  does  not  have  to  strive 
against  untoward  circumstances;  it  simply  develops  seeds  or  spores 
and  passes  into  a  resting  stage.  In  this  state  it  does  not  need  air  or 


82  ANTHRAX 

food.  It  is  inactive  and  is  only  potentially  alive.  When  conditions 
become  favorable,  the  spores  develop  into  the  vegetative  form.  The 
capability  of  passing  from  one  form  to  another  is  a  great  factor  in 
protecting  the  bacillus  against  destructive  agencies.  Each  bacillus 
produces  only  one  spore.  There  is,  therefore,  no  multiplication  in  the 
exercise  of  this  function.  The  purpose  seems  to  be  solely  to  protect 
the  life  of  the  individual.  When  times  are  good  with  plenty  of  air 
and  an  abundance  of  suitable  food,  life  seems  to  proceed  merrily  and 
the  organism  multiplies  abundantly.  When  times  are  hard,  with  inade- 
quate air  or  food,  the  bacillus  drops  into  the  resting  stage  in  which  it 
has  no  needs  and  awaits  a  change  for  the  better.  When  anthrax 
spores  are  brought  under  favorable  conditions  each  spore  develops  into 
a  rod  which  for  a  while  carries  on  one  end  the  waste  remnant  of  the 
spore.  Vegetative  life  with  multiplication  by  fission  begins  anew. 

There  are  some  strains  of  the  bacillus  which  apparently  are  not 
able  to  pass  into  the  resting  stage  under  any  conditions.  These  are 
known  as  asporogenous  strains.  According  to  Eisenberg,  anthrax 
bacilli  are  of  two  varieties  or  races,  of  different  "biological  dignity," 
one  sporogenous  and  the  other  asporogenous,  and  each  breeds  true 
through  all  generations.  Roux  converts  the  sporogenous  into  the 
asporogenous  variety  by  the  following  method : 

Bacilli  grow  with  the  formation  of  spores  in  bouillon  to  which 
from  two  to  six  parts  per  ten  thousand  of  phenol  has  been  added. 
When  the  phenol  has  been  increased  to  twenty  parts  per  ten  thousand 
there  is  no  growth.  Between  these  limits  the  bacilli  grow  without 
spore  formation.  Bacilli  kept  in  these  intermediate  solutions  for  from 
eight  to  ten  days  permanently  lose  even  in  following  generations  the 
ability  to  produce  spores. 

The  resistance  of  the  anthrax  bacillus  depends  on  the  presence  or 
absence  of  spores.  The  latter  are  among  the  most  stabile  and  resistant 
forms  of  pathogenic  bacteria.  They  are  more  easily  killed  than  the 
spores  of  certain  nonpathogenic  organisms,  such  as  the  potato 
bacillus.  Anthrax  spores  on  silk  threads  supply  standards  for  testing 
the  relative  efficiency  of  disinfectants.  Spores  in  cultures  eighteen 
years  old  have  been  found  not  only  viable  but  capable  of  developing 
into  virulent  vegetative  organisms.  Bouillon  cultures  of  the  vegetative 
form  are  sterilized  by  heat  at  80  C.  (176  F.)  for  one  minute,  while 


ANTHRAX  S3 

boiling  for  at  least  three  minutes  is  necessary  to  insure  the  destruction 
of  the  spores.  Dry  heat  at  100  C.  (212  F.)  must  be  continued  for 
two  hours  in  order  to  destroy  the  vegetative  form,  while  three  hours 
at  140  C.  (284  F.)  are  necessary  to  exterminate  the  spores.  The 
effect  of  direct  sunlight  on  the  two  forms  has  been  studied  with  vary- 
ing and  even  contradictory  results.  This  is  easily  understood  when 
we  think  of  the  many  variable  factors,  such  as  thickness  of  layer, 
intensity  of  light  and  temperature,  entering  into  such  experiments  and 
influencing  the  findings.  According  to  Moment,  drops  of  dried  bouil- 
lon cultures,  with  the  air  temperature  at  from  25  to  35  C.  (77  to  95 
F.),  are  destroyed  when  exposed  to  direct  sunlight  within  from  six  to 
fifteen  hours  in  the  vegetative  form  and  after  one  hundred  hours  when 
spores  are  present.  The  ordinary  disinfectants,  as  generally  used, 
destroy  the  vegetative  forms  but  are  not  certain  in  their  action  on 
spores.  Geppert  found  that  after  from  two  to  three  hours  in  corrosive 
sublimate  (1:  1,000)  all  spores  are  not  killed. 

We  may  be  thankful  that  this  bacillus,  armed  as  it  is  with  so  many 
advantages  and  possessed  of  weapons  effective  against  so  many  species 
of  animals,  has  some  powerful  antagonists.  Were  this  not  true  the 
world  might  have  been  depopulated  by  the  unopposed  activity  of  this 
microscopic  organism.  As  it  is,  it  is  possible  that  the  extinction  of 
certain  species  of  animals  may  have  resulted  from  this  infection. 
Many  other  bacteria  are  markedly  antagonistic  and  destructive  to  the 
anthrax  bacillus.  Chief  among  those  in  which  this  function  has  been 
observed  and  studied  is  the  Bacillus  pyocyaneus.  In  mixed  cultures 
of  these  organisms  the  pyocyaneus  only  survives.  It  not  only  survives 
but  it  seems  to  feed  on  the  anthrax  bacilli.  If  across  a  gelatine  plate 
parallel  lines  be  drawn  alternatingly  with  needles  moist  with  cultures 
of  the  two  bacilli,  the  pyocyaneus  only  will  develop.  If  crosses  be 
made  with  the  needles  the  pyocyaneus  only  will  develop  at  the  cross. 
The  pyocyaneus  develops  a  bacteriolytic  body  known  as  pyocyanase, 
which  readily  digests  and  destroys  the  anthrax  bacillus.  This  seems  to 
be  a  proteolytic  ferment,  but  unlike  similar  bodies  it  is  not  destroyed 
by  prolonged  boiling.  This  fact  has  led  to  the  suggestion  that  it 
destroys  the  anthrax  bacillus  by  osmotic  changes.  A  few  drops  of  a 
solution  of  pyocyanase  added  to  a  bouillon  culture  of  anthrax  leads 
to  a  speedy  dissolution  of  the  bacilli.  Moreover,  laboratory  animals, 


84  ANTHRAX 

sheep,  rabbits,  and  guinea-pigs,  infected  with  anthrax,  have  been  cured 
by  injections  of  pyocyanase.  Among  other  less  thoroughly  studied 
antagonistic  bacteria  are  the  staphylococcus,  the  streptococcus  and  the 
pneumonia  bacillus. 

Certain  fluids  of  the  animal  body  have  a  destructive  action  on  the 
anthrax  bacillus.  Strange  to  say,  this  does  not  seem  to  have  any 
marked  effect  on  the  susceptibility  of  the  animal  to  this  infection.  The 
blood  serum  of  the  rabbit  in  vitro  is  markedly  bactericidal.  Accord- 
ing to  Pane  1  c.c.  of  such  serum  will  destroy  8,000  anthrax  bacilli  and 
still  the  rabbit  is  easily  susceptible  to  inoculation  with  this  bacillus. 
The  destructive  agent  in  rabbit's  serum  seems  to  be  a  ferment,  inas- 
much as  it  is  destroyed  by  a  temperature  of  56  C.  (132.8  F.).  The 
blood  of  the  rat,  an  animal  which  has  some  marked  resistance  to 
anthrax  inoculation,  is  highly  bactericidal  to  this  organism.  This  is 
believed  to  be  due  to  the  relatively  high  alkalinity  of  the  rat's  blood. 
Fodor  showed  many  years  ago  that  arterial  blood  is  destructive  to  the 
anthrax  bacillus. 

While  mammals  are  susceptible  to  anthrax  they  differ  in  this  par- 
ticular widely  in  degree.  Epidemics  are  most  common  in  cattle  and 
sheep  and  the  latter  are  easily  inoculable  with  pure  cultures,  while  the 
former  are  unexpectedly  more  resistant  and  require  larger  doses. 
Algerian  sheep  are  highly  resistant.  Hogs  are  less  susceptible  than 
cattle  and  sheep,  and  here  again  there  is  marked  variation  in  varieties, 
American  and  English  breeds  being  more  susceptible  than  those  of 
Hungary.  Among  our  more  valuable  domestic  animals  horses  are 
somewhat  more  resistant  than  cattle  and  sheep  but  in  some  epidemics 
they  die  in  great  numbers.  Dogs  are  least  susceptible  but  succumb 
to  intravenous  inoculations.  Goats  resemble  sheep  in  susceptibility. 
Of  the  smaller  laboratory  animals,  the  rat  is  the  least  susceptible, 
while  rabbits,  guinea-pigs,  and  mice  succumb  to  every  form  of  inocu- 
lation. It  is  said  that  a  single  bacillus  will  kill  a  guinea-pig.  All 
menagerie  animals  are  susceptible.  Birds  are  highly  resistant  and 
epidemics  among  them  are  not  known,  but  all  may  be  infected  arti- 
ficially. Frogs  are  highly  refractory  but  the  disease  may  be  induced 
in  them.  Snails  are  said  to  be  wholly  refractory.  Turtles  and  fish  are 
susceptible  to  artificial  inoculation,  the  former  readily  so. 


ANTHRAX  85 

Avenues  of  Infection. — The  virus  may  find  admission  to  the  animal 
body  subcutaneously,  intravenously,  by  feeding  or  by  inhalation.  A 
break  in  the  continuity  of  the  skin  or  mucous  membrane  may  afford  a 
port  of  entry.  Even  in  feeding  the  point  of  entry  may  be  in  the 
mouth,  pharynx  or  esophagus,  caused  by  a  slight  wound.  Especially 
is  this  true  in  animals  in  which  slight  wounds  may  be  caused  by  hard 
bits  of  food,  dust  or  other  accidental  constituents.  The  dried  spores 
may  infect  through  any  of  these  avenues  quite  as  effectively  as  the 
vegetative  forms.  The  spores  are  especially  suitable  for  infection  by 
inhalation.  Moreover,  in  feeding,  the  spores  are  more  resistant  than 
the  vegetative  forms  to  the  acid  of  the  gastric  juice.  While  the  blood 
may  be  free  from  bacilli  in  the  first  stage  of  the  disease  and  while  in 
rare  non-fatal  cases  the  infection  may  remain  localized,  in  most 
instances  the  blood  becomes  a  vehicle  for  the  transport  of  the  virus 
and  it  reaches  every  part  of  the  body.  The  bacilli  are  eliminated  from 
infected  animals  with  the  urine  and  feces.  They  have  been  found  in 
milk  drawn  from  sick  cows  a  short  time  before  death.  The  fetus  in 
utero  may  become  infected.  This  has  been  observed  in  both  lower 
animals  and  man.  In  epidemics,  fields,  barnyards  and  stalls  become 
infected  and  the  most  common  port  of  entry  is  the  mouth.  The  feces 
and  urine  of  infected  animals  pollute  all  about  them  and  the  virus  is 
easily  and  quickly  transferred  to  the  well.  Naturally,  anthrax  devel- 
ops, in  epidemics,  among  men  who  are  brought  into  close  contact  with 
the  sick  animals.  In  Russia  from  1904  to  1909  the  average  annual 
deaths  from  anthrax  among  men  numbered  sixteen  thousand ;  in  Italy 
from  1890  to  1900,  about  two  thousand  one  hundred.  In  1910  the 
number  of  persons  infected  with  anthrax  in  Germany  is  given  as  2S7, 
with  40  deaths.  Certain  occupations,  such  as  butchers,  tanners,  sheep 
shearers,  furriers  and  glove  makers,  shoemakers,  saddlers  and  harness 
makers,  dealers  in  hay  and  grain,  and  wool-sorters,  are  especially 
exposed  to  this  infection.  The  primary  infection  in  man  is  most  fre- 
quently through  slight  wounds  on  the  skin  where  malignant  pustules 
form.  The  lungs  may  be  infected  through  inhalation.  Intestinal 
infection  in  man,  though  infrequent,  has  been  reported.  Fruit  and 
vegetables  may  be  polluted  by  the  urine  or  feces  of  animals  and  may 
carry  the  virus  into  the  alimentary  canal. 


CHAPTER    X 


DYSENTERY 

History. — Epidemics  characterized  by  frequent,  painful  and  bloody 
discharges  from  the  bowels  are  mentioned  in  the  oldest  medical  rec- 
ords. They  have  been  observed  in  both  civil  and  military  life  and 
have  at  times  contributed  largely  to  the  high  mortality  of  cities  and 
camps.  However,  no  differentiation  of  the  diseases  marked  by  these 
general  symptoms  was  possible  before  the  development  of  the  science 
of  bacteriology  began.  As  early  as  1875  Losch  of  St.  Petersburg 
reported  the  presence  of  amebas  in  the  stools  of  a  patient  with  bloody 
dysentery.  Some  years  later  (1886)  Kartulis  made  like  reports  con- 
cerning the  dysentery  of  Egypt.  These  widely  separated  observers 
were  the  first  scientific  contributors  to  our  knowledge  of  what  is 
known  as  amebic  dysentery.  When  work  along  this  line  was  taken  up 
in  dfferent  parts  of  the  world,  it  became  evident  that  there  are  two 
forms  of  this  disease,  amebic  and  bacillary.  Further  discussion  of  the 
former  will  be  reserved  for  another  section. 

When  it  was  shown  that  amebas  are  not  found  in  many  severe 
epidemics  of  dysentery,  so  many  investigators  in  different  parts  of 
the  world  began  the  search  for  other  causal  agents  and  so  many  find- 
ings were  reported,  that  it  is  now  quite  impossible  to  say  with  abso- 
lute certainty  to  whom  the  greatest  credit  is  due.  There  have  been 
many  claims  to  priority  and  it  is  possible  that  the  names  now  gen- 
erally attached  to  the  several  bacilli  known  to  produce  this  disease 
are  not  those  of  the  men  who  first  saw  them.  However,  I  will  not 
add  to  the  controversy  over  these  matters  but  will  use  the  names 
generally  employed  by  writers  on  this  subject. 

In  1898  Shiga  showed  that  amebas  were  not  found  in  the  severe 
epidemics  of  dysentery  prevalent  in  Japan  at  that  time,  but  he  did 
find  in  the  stools  during  life  and  in  the  body  after  death  a  well- 
defined  and  easily  recognized  bacillus.  Since  this  organism  was  found 
in  all  cases,  and  since  its  cultures  were  agglutinated  by  high  dilutions 
of  blood  serum  of  those  ill  with  this  disease,  Shiga  felt  justified  in 


88  DYSENTERY 

claiming  that  he  had  found  the  specific  cause,  and  subsequent  studies 
by  others  have  confirmed  this  claim.  This  organism  is  now  generally 
known  as  the  Shiga  bacillus. 

Two  years  later  (1900)  Flexner,  in  a  report  of  an  expedition  to 
investigate  the  diseases  prevalent  in  the  Philippines,  described  a  bacil- 
lus found  in  epidemics  on  these  islands.  It  also  was  present  in  all  cases 
and  agglutinated  with  dilutions  of  the  blood  serum  of  the  sick.  There 
was  for  a  time  much  discussion  about  the  identity  of  these  two  organ- 
isms. It  would  be  profitless  to  follow  these  discussions  since  it  is  now 
generally  admitted  that  the  differences  are  sufficient  to  justify  the  con- 
clusion that  they  are  different  species,  and  this  is  now  known  as  the 
"Flexner"  bacillus.  There  are  two  other  bacilli  capable  of  causing 
dysentery.  These  are  varieties  of  the  Flexner  organism.  One  is 
known  as  the  "His-Russell,"  and  the  other  as  the  "Strong"  bacillus. 

The  Shiga  Bacillus. — This  is  a  small  plump  rod  with  rounded  ends. 
It  was  at  first  believed  to  be  motile,  but  closer  study  shows  that  it 
has  no  flagellae  and  no  active  motion,  although  it  demonstrates  the 
Brownian  movements  in  a  marked  degree.  It  is  sporeless  and  ordi- 
narily it  needs  frequent  transplantation  in  order  to  keep  it  alive.  How- 
ever, according  to  Martini,  if  an  agar-culture  tube  be  hermetically 
sealed  the  rods  disintegrate  into  a  granular  debris  which  is  not  easily 
stained  and  shows  no  rods.  If  this  granular  mass,  even  after  a  year, 
be  placed  in  fresh  medium,  normal  rods  develop.  This  observation 
has  been  confirmed  by  similar  findings  with  the  plague  bacillus  and  it 
should  be  more  closely  and  thoroughly  studied.  Fresh  cultures  have 
a  sperm-like  odor,  while  older  ones  develop  trimethyl  and  ammonia. 
Very  old  growths  have  a  strong  and  penetrating  fecal  smell.  It  takes 
the  ordinary  stains  easily,  but  the  staining  is  not  always  uniform ;  some- 
times it  is  polar.  It  develops  on  ordinary  media  without  any  char- 
acteristic exhibitions.  Culturally  it  is  distinguished  from  the  Flexner 
and  related  dysentery  bacilli  by  the  fact  that  it  develops  no  acid  when 
grown  on  media  containing  mannite,  maltose  or  saccharose.  The 
Shiga  bacillus  is  furthermore  distinguished  from  the  other  organisms 
by  the  development  of  a  soluble  toxin.  This  will  be  discussed  in  more 
detail  later. 

The  Shiga  bacillus  is  not  highly  resistant  to  unfavorable  condi- 
tions. It  is  easily  destroyed  by  the  usually  employed  disinfectants, 


DYSENTERY  89 

both  the  soluble  and  the  gaseous  forms.  However,  it  retains  both 
viability  and  virulence  for  days  when  deposited  on  clothing  or  food. 
It  soon  dies  out  in  running  water  and  epidemics  of  bacillary  dysentery 
due  to  infected  water  are  probably  rare.  In  sterilized  water  it  lives  for 
many  weeks,  but  in  the  presence  of  the  usual  saprophytic  bacteria  of 
water  it  soon  dies  out. 

The  Flexner  Bacillus. — Morphologically,  culturally  and  tinctorially 
this  organism  is  but  little  different  from  the  Shiga  bacillus.  It,  how- 
ever, produces  indol  in  peptone  cultures  more  abundantly;  produces 
acid  in  mannite  cultures;  rapidly  reduces  nitrates  to  nitrites;  and 
elaborates  a  soluble  toxin,  either  not  at  all  or  only  in  small  amount. 
These  differences  in  function  rather  than  in  form,  lead  to  the  con- 
clusion that  the  two  organisms  are  of  different  species.  The  His- 
Russell  organism  is  a  variety  or  strain  of  the  Flexner  bacillus.  It 
produces  indol  more  slowly,  reduces  nitrates  less  energetically,  and 
decomposes  mannite,  but  is  without  action  on  maltose  and  saccharose. 
The  Strong  organism  is  even  more  closely  related  to  the  Flexner 
bacillus  and  in  fact  there  seems  to  be  no  constant  differences  when 
many  strains  of  both  are  studied.  The  Shiga  bacillus  with  its  sub- 
varieties  is  known  as  the  dysentery  bacillus  rich  in  toxin  production, 
and  the  others  as  poor  in  this  product.  The  latter  are  found  to  be  the 
more  stabile.  They  are  not  so  easily  overgrown  by  saprophytic  bac- 
teria; they  retain  their  vitality  for  a  longer  time  under  adverse  con- 
ditions and  they  are  not  so  easily  destroyed  by  disinfectants.  They 
may  persist  for  many  days  in  drinking  water,  for  many  weeks  on 
clothing,  and  cultures  need  to  be  transplanted  only  every  second  or 
third  month. 

Rabbits,  mice,  dogs,  goats  and  horses  are  highly  susceptible  to  sub- 
cutaneous, intra-abdominal  and  intravenous  inoculations  with  these 
bacteria,  especially  the  Shiga  bacillus.  Very  minute  doses  introduced 
by  these  avenues  cause  acute  fever  with  paralytic  symptoms  in  the 
extremities,  diarrheic  stools  with  mucus  and  blood,  then  a  rapidly  fall- 
ing temperature  ending  in  death:  Post-mortem  examination  shows 
an  inflammatory  condition  of  the  kidneys,  lungs  and  the  mucous  mem- 
brane of  the  intestinal  tract.  The  bacilli  are  found  in  these  cases  in 
the  stools,  in  the  blood,  and  in  the  various  organs.  With  still  smaller 
doses  the  disease  is  more  chronic  and  the  lesions  are  more  advanced 


90  DYSENTERY 

with  necrosis  of  the  intestinal  epithelium  and  ulceration  in  the  large 
intestine.  These  effects  are  produced  by  both  living  and  dead  bacilli 
of  the  Shiga  type,  also  with  filtered  cultures.  This  shows  that  the 
nature  of  the  process  is  an  intoxication  rather  than  a  pure  infection. 
Even  one  one-hundredth  of  a  loop  of  a  culture  may  induce  these 
symptoms  and  lesions  in  mice.  Strange  to  say,  the  guinea-pig  is 
relatively  resistant  to  this  organism.  From  the  researches  of  Gay  we 
learn  that  the  horse  shows  marked  elevation  of  temperature,  with 
prostration  and  labored  breathing  when  treated  with  one-fourth  the 
minimum  fatal  dose  for  guinea-pigs. 

There  has  been  much  controversy  concerning  the  nature  of  the 
soluble  toxin  found  in  cultures  of  the  Shiga  bacillus.  Some  claim  that 
it  is  a  true  toxin,  a  secretion  of  the  bacillary  cells,  while  others  con- 
tend that  it  is  an  autolytic  product,  resulting  from  the  cleavage  of 
the  bacilli.  Antitoxic  sera  in  variety  have  been  made  and  have  been 
used  for  both  prevention  and  cure.  Living  and  dead  cultures  have 
been  used  in  the  preparation  of  the  toxins,  and,  as  happens  when 
bacterial  cell  substance  is  repeatedly  injected,  many  animals  die  in  the 
process  of  immunization.  There  is  no  standard  method  of  preparing 
the  antitoxin  as  there  is  for  diphtheria.  It  follows  that  the  antitoxic 
sera  are  not  of  uniform  value  and  there  is  still  some  doubt  as  to 
whether  their  effects  should  be  ascribed  to  bactericidal  or  antitoxic 
properties.  Gay  has  obtained  a  serum  by  treating  horses  with 
Flexner's  bacillus,  and  has  treated  cases  of  dysentery  with  good  results, 
but  Escherich  in  Vienna  did  not  find  it  so  valuable.  Numerous  observ- 
ers have  reported  great  reduction  in  the  mortality  in  cases  of  Shiga 
infection  by  treatment  with  the  specific  antitoxin. 

All  attempts  to  induce  typical  dysentery  in  ordinary  laboratory  ani- 
mals by  feeding  with  dysentery  bacilli  have  failed.  It  is  true  that 
massive  doses  may  cause  some  intestinal  inflammation  with  loose  stools, 
but  many  bacteria  will  bring  about  this  result.  In  apes  the  disease 
may  be  induced  by  feeding,  and  it  is  stated  that  dysentery  is  sometimes 
epidemic  among  these  animals.  This  is  certainly  true  of  confined 
animals,  one  such  epidemic  having  been  observed  in  Paris,  and  another 
in  Manila.  Subcutaneous  injections  of  dead  bacilli  in  man  have  been 
used  for  vaccination  purposes,  but  quite  naturally  the  value  of  such 
a  procedure  must  remain  undetermined  until  it  is  done  on  a  large 


DYSENTERY  91 

number  of  persons  living  in  the  midst  of  epidemic  dysentery.  Liidke 
vaccinated  himself  in  this  way,  but  later  became  infected  while  work- 
ing with  living  cultures.  He,  therefore,  concludes  that  if  subcutaneous 
injections  of  dead  cultures  have  any  protective  value,  it  is  of  short 
duration.  In  a  local  epidemic  in  an  insane  asylum  Fuksch  vaccinated 
the  men  and  left  the  women  without  treatment,  and  states  that  the 
disease  did  not  spread  further  among  the  former  while  it  continued 
among  the  latter.  Shiga  in  1898-1900  vaccinated  ten  thousand 
Japanese  in  localities  in  which  dysentery  was  prevalent  and  found  that 
this  procedure  did  not  reduce  the  morbidity  but  had  a  most  marked 
and  gratifying  effect  on  the  mortality.  In  some  localities,  while  the 
death-rate  among  the  unvaccinated  reached  from  30  to  40  per  cent., 
there  were  no  deaths  among  the  vaccinated.  The  same  investigator 
vaccinated  large  numbers  of  the  Japanese  troops  in  the  war  with 
Russia.  At  this  time  he  suspended  dead  bacilli  in  antitoxic  serum  and 
made  three  injections  at  intervals  of  three  or  four  days,  increasing 
the  size  of  the  dose  at  each  injection. 

There  can  be  no  doubt  concerning  the  causal  relation  of  these 
bacilli  to  dysentery  in  man.  As  has  been  stated,  high  dilutions  of  the 
blood  of  those  sick  agglutinate  cultures  of  these  bacilli.  This  is  posi- 
tive evidence,  but  there  is  confirmatory  proof.  Strong  fed  pure  cul- 
tures of  the  Shiga  bacillus  to  two  criminals  sentenced  to  death,  and 
both  developed  typical  dysentery.  Jehle  drank  mixed  Shiga  and  Flex- 
ner  cultures  and  developed  the  disease  on  the  third  day.  He  found 
both  bacilli  in  his  stools.  Several  accidental  laboratory  infections  have 
occurred. 

Each  of  these  bacilli  produce  typical  dysentery  with  characteristic 
symptoms  and  lesions.  The  Shiga  bacillus  is  the  most  virulent,  but 
otherwise  the  results  are  the  same.  Close  study  shows  that  the  varie- 
ties of  these  bacilli  might  be  multiplied,  but  while  this  is  of  scientific 
interest  it  is  not  of  great  practical  importance.  These  bacilli  are  dis- 
tributed all  over  the  world,  having  been  found  in  all  climes  and  among 
all  conditions  of  men. 

Sources  of  Infection. — Like  typhoid  fever,  dysentery  is  always  due 
to  the  transfer  of  the  excreta  of  one  person  to  the  ingesta  of 
another.  In  the  great  majority  of  instances  the  infection  is 
transferred  through  contact,  which  may  be  direct  or  indirect.  The 


92  DYSENTERY 

prevalence  of  dysentery  is  determined  by  the  extent  to  which  fecal 
contamination  exists.  The  disease  is  most  abundant  when  fecal  dis- 
position is  most  primitive.  With  improvement  in  the  latter,  the  dis- 
ease grows  less.  Thirty  years  and  more  ago,  dysentery  under  various 
names,  such  as  "mucous  and  bloody  diarrhea"  and  "bloody  flux," 
reaped  a  rich  harvest,  especially  among  children,  in  various  sections 
of  this  country.  As  methods  of  the  disposal  of  fecal  matter  grew 
more  efficient,  the  death-rate  from  this  disease  decreased.  It  decreased 
at  first  in  cities,  with  the  introduction  of  water  closets,  then  it  grew 
less  in  villages  in  which  the  same  improvement  was  inaugurated  and 
lastly  its  highest  prevalence  was  in  the  less  progressive  and  more 
ignorant  communities.  Its  dependence  on  ignorance  and  filth  for  its 
dissemination  is  shown  in  the  frequency  of  outbreaks  in  insane  asylums 
and  especially  in  wards  occupied  by  those  who  pollute  themselves,  their 
clothing  and  bedding,  and  even  the  walls  of  their  rooms  with  fecal 
matter.  In  primitive  places  there  are  not  even  privy  vaults,  and  stools 
are  deposited  at  random  on  the  ground.  Everything  about  the  indi- 
vidual home  and  throughout  the  village  becomes  soiled  with  fecal 
matter.  These  are  the  localities  in  which  dysentery  most  abundantly 
flourishes.  With  typhoid  fever,  it  has  spread  through  camps  and 
decimated  armies.  It  has  accompanied  military  and  civil  explorations 
even  into  uninhabited  regions  and  has  flourished  wherever  man  has 
found  even  a  temporary  abiding  place  and  has  surrounded  and  befouled 
himself  with  his  own  excretions.  This  does  not  mean  that  it  may 
originate  de  novo,  for  it  does  not,  but  the  sick  and  the  well  may  long 
harbor  the  bacilli  in  their  intestines  and  plant  it  over  wide  regions  in 
their  stools.  Hands,  the  person,  clothing,  bedding,  food  and  water 
may  bear  the  infection.  From  the  dirty  hands  of  the  milker,  the  cook 
or  the  waiter  these  organisms  may  find  their  way  into  the  food.  Those 
recovering  from  the  disease  may  continue  for  weeks  as  veritable  cul- 
ture flasks  for  the  growth  and  distribution  of  this  virus.  Others  may 
carry  the  bacilli  without  developing  the  disease  themselves.  Flies  and 
possibly  other  insects  aid  in  its  distribution.  While  the  bacilli  are 
not  spontaneously  generated  in  filth,  they  are  widely  disseminated  and 
they  flourish  in  polluted  places. 


CHAPTER    XI 


TYPHUS    FEVER 
HISTORY 

There  are  medical  historians  who  find  evidence  of  the  existence  of 
typhus  fever  among  the  ancient  Hebrews  and  their  contemporaries, 
but  this  is  a  matter  of  conjecture.  While  this  disease  has  long  been 
known  as  morbus  pauperum,  associated  with  want  and  famine,  we 
must  not  infer  that  it  is  the  only  fever  which  develops  and  thrives 
among  the  needy  and  in  times  of  scarcity  of  food  and  other  privations. 
Poverty  and  overcrowding  favor  the  development  and  distribution  of 
many  infections.  Some  of  the  cases  reported  by  Hippocrates  in  his 
book  on  epidemics  are  certainly  suggestive  of  typhus. 

The  following  is  the  report  of  a  case,  now  believed  to  have  been 
typhus,  made  by  Hippocrates,  as  translated  by  Adams : 

In  Thasus  the  wife  of  Dealces,  who  was  lodged  on  the  plain,  from  sorrow 
was  seized  with  an  acute  fever,  attended  with  chills.  From  first  to  last  she 
wrapped  herself  up  in  her  bedclothes;  still  silent,  she  fumbled,  picked,  bored 
and  gathered  hairs  (from  the  covers);  tears  and  again  laughter;  no  sleep; 
bowels  irritable,  but  passed  nothing;  when  directed,  drank  a  little;  urine  thin 
and  scanty ;  to  the  touch  of  the  hand  the  fever  was  slight ;  coldness  of  extremi- 
ties'. On  the  ninth  (day)  talked  much  incoherently,  and  again  became  com- 
posed and  silent.  On  the  fourteenth,  breathing  rare,  large,  at  intervals;  and 
again  hurried  respiration.  On  the  sixteenth,  looseness  of  the  bowels  from  a 
stimulating  clyster ;  afterwards  she  passed  her  drink,  nor  could  retain  .anything, 
for  she  was  completely  insensible;  skin  parched  and  tense.  On  the  twentieth 
much  talk  and  again  became  composed;  loss  of  speech;  respiration  hurried. 
On  the  twenty-first  she  died.  Her  respiration  throughout  was  rare  and  large ; 
she  was  totally  insensible;  always  wrapped  up  in  her  bedclothes;  either  much 
talk  or  complete  silence  throughout.  Phrenitis. 

The  great  Athenian  pestilence  so  well  described  by  Thucydides  was 
either  typhus  or  the  pneumonic  form  of  the  plague.  Livy  and  Tacitus 
tell  of  many  epidemics  in  the  classical  period  of  Rome.  Some  of  these 
undoubtedly  were  epidemics  of  the  plague,  while  the  descriptions  of 
others  suggest  typhus.  The  dark  ages  were  so  overshadowed  by  dis- 


94  TYPHUS    FEVER 

ease  and  superstition  that  medical  records  of  value  are  almost  wholly 
wanting.  In  the  siege  of  Granada  in  1489  no  less  than  17,000  of 
Ferdinand's  soldiers  died  of  a  fever  which  was  designated  as  "Tabar- 
dillo,"  on  account  of  the  spots  appearing  on  the  skin.  This  term  is 
still  one  of  the  Spanish  names  for  typhus.  In  the  sixteenth  century 
two  Italian  physicians,  Fracastorius  of  Verona  and  Cardanus  of  Pavia, 
described  typhus  fever  so  plainly  that  there  can  be  no  doubt  about 
the  disease  which  then  prevailed.  In  four  years  (1550-1554)  more 
than  one  million  people  in  Tuscany  were  destroyed  by  typhus.  Fra- 
castorius describes  the  disease  as  "Febris  pestilens,"  and  states  that  it 
was  vulgarly  known  as  "Lenticulae"  or  "Puncticula."  He  says  from 
the  fourth  to  the  seventh  day  red  eruptions  appear  on  the  arms,  chest, 
and  back.  They  resemble  flea  bites,  only  are  somewhat  larger.  They 
also  resemble  lentils  and  from  this  comes  the  popular  name.  The  most 
marked  symptoms  mentioned  are  great  prostration,  feeble  pulse, 
injected  conjunctivae,  and  low  muttering  delirium.  Some  are  som- 
nolent while  others  are  excited  and  wakeful,  while  in  still  others  these 
states  alternate.  The  disease  lasted  from  seven  to  fourteen  days, 
rarely  longer.  The  majority  of  those  who  were  bled  died  and  a  sup- 
porting treatment  proved  best.  Cardanus  and  other  Italian  physicians 
stated  that  many  of  the  practitioners  of  the  time  mistook  this  disease 
for  measles,  and  Massa  of  Venice  wrote  on  the  distinctions  between 
the  eruptions  of  this  disease  and  those  of  measles  and  smallpox.  About 
the  middle  of  the  sixteenth  century  this  disease  was  widely  prevalent 
in  France  and  Coyttarus  of  Poitiers  wrote  a  monograph  on  it,  under 
the  title  "De  Febribus  Purparatis"  and  somewhat  later  Ambrose  Pare, 
the  distinguished  surgeon,  wrote  of  "febris  pestilens"  which  was 
marked  by  eruptions  resembling  the  bites  of  fleas  or  bed  bugs. 

Morbus  Hungaricus  appeared  in  the  army  of  Maximilian  II  in 
Hungary  in  1566,  and  soon  spread  over  the  greater  part  of  Europe. 
Sennertus  and  others  have  left  descriptions  of  this  epidemic.  The 
skin  was  marked  by  flea-bite  eruptions.  Headache  was  intense  and 
followed  by  delirium.  In  some,  the  tongue  became  black,  parotid 
abscesses  developed  and  gangrene  of  the  limbs  occurred. 

Under  the  title,  "Febris  maligna  puncticularis  seu  peticularis," 
Castro  of  Verona  (1580)  pictured  the  symptoms.  The  pulse  is  small 
and  weak;  the  tongue  dry  and  black;  the  face  and  eyes  greatly  con- 


TYPHUS    FEVER  95 

gested;  delirium,  followed  by  stupor  deepening  into  coma;  parotid 
abscesses  in  some,  the  eruption  appearing  about  the  seventh  day  and 
the  disease  continuing  from  fourteen  to  twenty  days.  Castro  says 
that  this  disease  was  known  to  the  French  as  "La  Pourpre;"  to  the 
Italians  as  "Petecchie ;"  to  the  Spaniards  as  "Tabardillo,"  and  to  the 
Germans  as  "Fleckfieber." 

During  the  sixteenth  century  typhus  fever  was  so  prevalent  in  the 
jails  of  England  that  the  disease  spread  among  the  court  officers  when 
prisoners  were  brought  before  them  for  trial.  This  happened 
repeatedly  and  gave  to  court  sessions  the  designation  of  "black  assizes." 
The  first  of  these  of  which  record  is  left  occurred  at  Cambridge  in  the 
thirteenth  year  of  the  reign  of  Henry  VIII  (1522).  The  justices, 
bailiffs,  gentlemen  and  other  persons  in  court  were  seized  with  a  fever 
which  proved  fatal  to  many.  The  most  notable  report  of  a  "black 
assize"  is  that  at  Oxford  in  the  twentieth  year  of  the  reign  of  Elizabeth 
(1577).  The  prisoner  was  Rowland  Jenks,  a  bookbinder  and  a  Roman 
Catholic,  who  was  charged  with  treason  and  profanity  of  the  protes- 
tant  religion.  He  was  sentenced  to  lose  his  ears.  The  trial  was  held 
at  Oxford  Castle,  July  4.  Several  prisoners  were  brought  into  court 
in  the  couurse  of  the  trial.  The  chronicle  states  that  "an  infectious 
damp  of  breath"  spread  through  the  room.  "Above  six  hundred  sick- 
ened in  one  night;  and  the  day  after,  the  infectious  air  being  carried 
into  the  next  village  sickened  there  more  than  an  hundred  more."  By 
the  twelfth  of  August  510  persons  perished.  "The  infection  arose 
from  the  nasty  and  pestilential  smell  of  the  prisoners  when  they  came 
out  of  the  jail,  two  or  three  of  whom  had  died  a  few  days  before  the 
assize  began."  The  disease  was  marked  by  loss  of  appetite,  headache, 
sleeplessness,  loss  of  memory,  deafness  and  delirium,  so  that  the  vic- 
tims behaved  like  madmen,  The  Catholics  saw  in  this  the  scourge  of 
God  for  the  unjust  punishment,  and  the  Protestants  attributed  it  to 
the  "diabolical  machinations  of  the  Papists." 

During  the  thirty  years  war  (1619-1648)  the  whole  of  central 
Europe  was  desolated  by  war,  famine  and  pestilence.  The  nature  of 
the  epidemic  is  plainly  shown  by  both  medical  and  lay  writers  and  its 
ravages  were  portrayed  in  both  prose  and  poetry.  One  verse  of  a  song 
runs  as  follows: 


96  TYPHUS    FEVER 

Per  omnes 

Burgundos  et  quas  stagnans  Arar  irrigat  urbes 
Insolita  exarsit  febris,  quae  corpora  rubris 
Inficiens  maculis   (triste  et  mirabile  dictu) 
Quarta  luce  frequens  fato  pendebat  acerbo. 
Pulsus  erat  minimus,  tremulusque  soporque 
Mens  vaga,  visque  labens;  totium  crassemque  rubensque 
Interdum  tenuae  instar  aquae. 

In  1658,  Morton  states  that  England  was  one  vast  hospital  filled 
with  the  victims  of  a  fever  with  "maculae  latae  et  rubicundae  morbillis 
similes  in  toto  corpore."  The  great  plague  of  London  (1665)  was 
preceded,  accompanied,  and  followed  by  typhus  and  some  of  the  most 
eminent  medical  men  of  the  time,  notably  Sydenham,  frequently  con- 
founded plague  and  typhus  in  the  reports  of  their  cases.  Under  the 
title,  "Febris  Petechialis  vera"  Hoffmann  of  Halle  (1700)  gave  an 
excellent  account  of  typhus  and  pointed  out  its  distinction  from  the 
plague,  which  he  designated  "Febris  Pestilens."  The  eighteenth  cen- 
tury saw  no  abatement  of  epidemics  of  typhus.  This  disease  had  long 
afflicted  Ireland  under  the  name  of  "Irish  ague,"  but  it  was  not  until 
1708  that  permanent  records  of  its  ravages  were  made.  From  that 
time  on  for  more  than  a  century  and  a  half  Ireland  was  afflicted  by  one 
epidemic  after  another,  just  as  fast  as  new  generations  supplied  a  crop 
of  susceptible  material.  The  historian  has  no  difficulty  in  showing  that 
each  exacerbation  was  coincident  with  a  period  of  great  want  and 
poverty,  but  this  was  a  chronic  condition  of  the  Emerald  Isle  during 
this  period.  The  people  were  oppressed  by  their  rulers,  divided  among 
themselves,  held  in  the  grossest  ignorance  and  fed  on  superstition. 
Most  of  those  who  had  enough  energy  emigrated  to  foreign  lands, 
thus  impoverishing  their  native  land  of  its  best  blood  to  such  an  extent 
that  it  has  not  yet  wholly  recovered.  An  account  of  one  epidemic  of 
typhus  in  Ireland  is  much  like  all  others.  Nothing  to  eat  but  potatoes ; 
and  an  adult  would  devour  ten  or  more  pounds  of  these  tubers  each 
day  in  the  vain  attempt  to  supply  his  body  cells  with  the  minimum 
amount  of  protein  demanded.  Driven  by  hunger  to  sell  the  cow,  fur- 
niture, and  even  his  clothing,  the  Irishman  and  his  family  huddled 
together  in  rags  and  filth,  while  vermin  fed  on  their  bodies  and  simul- 
taneously inoculated  them  with  typhus.  Murchison  says :  "In  Dublin, 


TYPHUS    FEVER  97 

the  servants  of  the  upper  classes  were  not  allowed  potatoes,  and  bread 
was  portioned  out  to  them  sparingly,  few  persons  had  more  than  a 
quartern  loaf  in  the  week.  The  poor  pawned  their  clothes,  and  even 
their  bedding  for  money  to  purchase  food,  and,  as  a  natural  conse- 
quence, it  was  common  for  several  members  of  one  family  to  sleep  in 
the  same  bed."  According  to  O'Connell,  eighty  thousand  Irish  died  in 
1740-1741  of  famine  and  spotted  fever  and  one-fifth  the  popula- 
tion of  Munster  perished.  Writing  of  a  nineteenth  century  epidemic 
of  typhus  in  Ireland,  Murchison  says : 

Extreme  distress  ensued.  The  four  pound  loaf  was  sold  in  Dublin  in  1817 
for  Is,  9d;  and  the  poor  throughout  Ireland  are  described  as  wandering  about 
the  country  gathering  nettles,  wild  mustard,  and  other  weeds,  to  satisfy  the 
cravings  of  hunger.  .  .  .  The  probable  population  of  Ireland  at  this  time 
was,  in  round  numbers,  six  million,  and  the  number  of  sick  was  estimated  at 
737,000,  or  at  about  one-eighth.  In  Dublin  alone  there  were  about  70,000  cases, 
making  about  one-third  of  the  inhabitants. 

Of  the  same  epidemic  Carleton  wrote: 

People  collected  at  the  larger  dairy  farms  waiting  for  the  cattle  to  be  blooded, 
so  that  they  might  take  home  some  of  the  blood  to  eat  mixed  with  a  little 
oatmeal.  The  want  .of  fuel  caused  the  pot  to  be  set  aside,  windows  and  crevices 
to  be  stopped,  washing  of  clothes  and  person  to  cease,  and  the  inmates  of  a 
cabin  to  huddle  together  for  warmth.  This  was  far  from  the  normal  state  of 
the  cottages  or  even  of  the  cabins,  but  cold  and  hunger  made  their  inmates 
apathetic.  Admitted  later  to  the  hospitals  for  fever,  they  were  found  bronzed 
with  dirt,  their  hair  full  of  vermin,  their  ragged  clothes  so  foul  and  rotten 
that  it  was  more  economical  to  destroy  them  and  replace  them  than  to  clean 
them. 

The  roads  were  filled  with  infected  vagrants  and  many  a  poor 
cottier  not  only  divided  what  he  had  in  alms,  but  by  giving  shelter  to 
the  wanderer  introduced  the  infection  into  his  humble  home,  while  "the 
dogs  of  the  gentry  kept  all  beggars  from  their  gates." 

The  last  great  Irish  famine  (1845-1848)  was  the  occasion  for  the 
prevalence  of  relapsing  fever  and  scurvy  as  well  as  typhus  fever.  This 
scourge  was  foreseen  in  the  development  of  the  potato  blight  and  was 
mitigated  somewhat  by  the  repeal  of  the  corn  laws  and  by  a  change 
in  the  navigation  laws  permitting  the  carrying  of  food  supplies  in  other 
than  British  bottoms.  At  that  time  Ireland  lived  almost  exclusively 
on  milk  and  potatoes.  Although  it  produced  more  than  enough  grain 


98  TYPHUS    FEVER 

to  feed  itself,  even  in  these  years  of  the  potato  blight,  most  of  this  had 
to  be  sent  to  England  to  pay  the  rents.  Years  before  both  Malthus 
and  Cobbett  had  protested  against  a  people  trying  to  live  so  largely 
on  potatoes.  The  former  wrote  as  follows: 

When  the  common  people  of  a  country  live  principally  on  the  dearest  grain, 
as  they  do  in  England,  on  wheat,  they  leave  great  resources  in  scarcity;  and 
barley,  oats,  rye  and  cheap  soup  and  potatoes  all  present  themselves  as  less 
expensive,  yet  at  the  same  time  wholesome  means  of  nourishment,  but  when 
their  habitual  food  is  the  lowest  in  the  scale,  they  appear  to  be  wholly  without 
resource  except  in  the  bark  of  trees  like  the  poor  Swedes ;  and  a  great  portion 
of  them  must  necessarily  be  starved. 

After  this  famine  the  Irish  ceased  to  rely  so  largely  on  the  potato, 
emigration  to  this  country  and  Canada  greatly  increased,  and  "the 
population  has  steadily  declined  and  the  well  being  of  the  people 
steadily  improved." 

Before  dismissing  the  subject  of  Irish  typhus  epidemics,  I  wish  to 
add  a  quotation  from  Creighton,  showing  that  the  case  mortality  in 
this  disease  is  higher  among  the  robust  and  well  fed  than  among  the 
weak  and  hungry.  "There  appeared  to  be  a  scale  of  malignity  in  the 
fevers  in  an  inverted  order  of  the  degree  of  misery.  The  most 
wretched  had  the  mildest  fever,  the  artisan  class  or  cottagers  had 
typhus  fatal  in  the  usual  proportion,  the  classes  living  in  comfort  had 
typhus  of  a  very  fatal  kind.  This  experience,  however  strange  it  may 
seem,  was  reported  by  medical  observers  everywhere  with  remarkable 
unanimity.  One  says  that  six  or  seven  of  the  rich  died  in  every  ten, 
others  say  one  in  three.  Forty-eight  medical  men  died  in  1847  in 
Munster,  most  of  them  from  fever;  in  Cavan  County  seven  medical 
men  died  from  fever  in  twelve  months  and  three  more  had  a  narrow 
escape  of  death;  two  of  the  three  physicians  sent  by  the  Board  of 
Health  to  the  coast  of  Connemara  died  of  fever.  Many  Catholic 
priests  died  as  well  as  some  of  the  established  Church  Clergy;  and 
there  were  numerous  fatalities  of  the  resident  gentry  and  among  others 
who  administered  the  relief.  Yet  a  case  of  fever  in  a  good  home  did 
not  become  a  focus  of  contagion ;  the  contagion  came  from  direct  con- 
tact with  the  crowds  of  starving  poor,  their  clothes  ragged  and  filthy, 
their  bodies  unwashed,  and  many  of  them  suffering  from  dysentery. 


TYPHUS    FEVER  99 

The  greater  fatality  of  fever  among  the  richer  classes  (of  course, 
with  a  much  smaller  number  of  cases)  has  been  a  commonplace  in 
Ireland  and  is  remarked  by  the  best  writers. 

Creighton  in  his  valuable  "History  of  Epidemics  in  Britain"  has 
shown  some  interesting  facts  concerning  typhus  in  England  during  the 
eighteenth  century.  I  will  follow  his  facts  but  will  draw  my  own 
conclusions.  During  the  half  century  from  1715  to  1765  England  was 
most  prosperous  financially.  Monied  men  built  up  great  fortunes  and 
the  necessities  of  life  were  abundant  and  cheap.  With  two  or  three 
exceptions  the  harvests  were  rich  and  grain  was  exported  in  great 
quantity.  Historians  state  that  under  the  first  two  Georges  there 
was  general  prosperity.  Even  Adam  Smith  speaks  of  "the  peculiarly 
happy  circumstances  of  the  country  during  the  reign  of  George  II 
(1726-1760)."  Hallam  speaks  of  this  period  "as  the  most  prosperous 
that  England  had  ever  experienced."  Lecky  says : 

All  the  evidence  we  possess  concurs  in  showing  that  during  the  first  three- 
quarters  of  the  century  the  position  of  the  poor  agricultural  classes  in  Eng- 
land was  singularly  favorable.  The  price  of  wheat  was  both  low  and  steady. 
Wages,  if  they  advanced  slowly,  appear  to  have  commanded  an  increased  pro- 
portion of  the  necessaries  of  life,  and  there  were  all  the  signs  of  growing 
material  well-being.  It  was  noticed  that  wheat  bread,  and  that  made  of  the 
finest  flour,  which  at  the  beginning  of  the  period  had  been  confined  to  the 
upper  and  middle  classes,  had  become  before  the  close  of  it  over  the  greater 
part  of  England  the  universal  food,  and  that  the  consumption  of  cheese  and 
butter  in  proportion  to  the  population  in  many  districts  almost  trebled.  Beef 
and  mutton  were  eaten  almost  daily  in  the  villages. 

Johnson  wrote: 

There  every  bush  with  nature's  music  rings, 
There  every  breeze  bears  health  upon  its  wings. 

However,  there  were  even  at  this  time  some  who  saw  beneath  the 
surface  of  abundance  and  prodigality.  An  economist,  Rogers,  pointed 
out  that  the  prosperity  was  all  on  the  side  of  the  ruling  classes  and  the 
capitalists,  while  the  laborers  were  in  "irremediable  poverty  and  with- 
out hope."  Their  wages  were  artificially  fixed  by  the  quarter  sessions 
and  they  were  kept  "in  a  condition  wherein  existence  could  just  be 
maintained." 


100  TYPHUS    FEVER 

Creighton  writes : 

But  the  Eighteenth  Century,  even  the  most  prosperous  part  of  it,  from  the 
accession  of  George  I  to  the  beginning  of  the  Industrial  Revolution  in  the 
last  quarter  or  third  of  it,  was  none  the  less  a  most  unwholesome  period  in 
the  history  of  England.  The  health  of  London  was  never  worse  than  in  those 
years,  and  the  vital  stastistics  of  some  other  towns,  such  as  Norwich,  are  little 
more  satisfactory. 

In  1782,  White  wrote  of  the  fever  in  London : 

The  annual  deaths  under  the  old  regime  exceeded  by  a  good  deal  the 
annual  births;  in  the  seven  years,  1728-35,  according  to  the  figures  in  the  parish 
registers,  the  burials  from  all  causes  were  3,488  and  the  baptisms  2,803,  an 
annual  excess  of  98  deaths  over  the  births  in  an  estimated  population  of  10,800 
(birth  rate  37  per  1,000,  death  rate  46  per  1,000). 

Creighton  says: 

The  mean  annual  deaths  were  never  higher  in  London,  not  even  in  plague 
times  over  a  series  of  years,  the  fever  deaths  keeping  pace  with  the  mortality 
from  all  causes,  and,  in  the  great  epidemic  of  typhus  in  1741,  making  about  a 
fourth  part  of  the  whole.  The  populace  lived  in  a  bad  atmosphere,  physical 
and  moral. 

It  is  stated  that  the  consumption  of  alcohol  in  London  amounted  to 
six  gallons  per  head  per  annum.  A  duty  of  20  shillings  per  gallon  did 
not  prevent  the  poor  from  getting  it,  and  large  quantities  of  gin  were 
smuggled  in  from  Holland.  In  1726  the  College  of  Physicians  pre- 
sented this  matter  to  the  House  of  Commons  with  the  following  state- 
ment: 

We  have  with  concern  observed  for  some  years  past  the  fatal  effects  of 
the  frequent  use  of  several  sorts  of  distilled  spirituous  liquor  upon  great  num- 
bers of  both  sexes,  rendering  them  diseased,  not  fit  for  business,  poor,  a  burthen 
to  themselves*  and  neighbors,  and  too  often  the  cause  of  weak,  feeble  and  dis- 
tempered children,  who  must  be,  instead  of  an  advantage  and  strength,  a  charge 
to  their  country. 

The  poor  in  London  were  crowded  into  small  quarters.  In  1737 
one  house  was  found  to  contain  eleven  married  couples  and  fifteen 
single  persons.  A  tax  was  levied  on  each  window  in  a  house  and 
each  window  in  cellar,  stairway  and  outhouse  was  counted  and  skylight 
included.  "No  window  or  light  shall  be  deemed  to  be  stopped  up 
unless  such  window  or  light  shall  be  stopped  up  effectually  with  stone 
or  brick  or  plaister  on  lath." 


TYPHUS    FEVER  101 

Debtors  were  thrown  into  prison  where  some  remained  for  years 
and  if  they  had  any  comforts  in  the  prison  they  had  to  pay  for  them. 
Jailors  grew  rich  out  of  the  necessities  of  their  wards.  Those  unable 
to  pay  were  crowded  into  unbelievably  small  quarters.  The  first  com- 
mission to  inquire  into  these  abuses  reported: 

George's  ward,  sixteen  feet  by  fourteen  and  about  eight  feet  high,  had 
never  less  than  thirty-two  in  it  all  last  year  and  sometimes  forty;  there  was  no 
room  for  all  to  lie  down,  one-half  the  number  sleeping  over  the  others  in  ham- 
mocks ;  they  were  locked  in  from  9  p.  m.  to  5  a.  m.  in  summer,  longer  in  winter, 
and  as  they  were  forced  to  ease  nature  within  the  room,  the  stench  was 
noisome  beyond  expression. 

It  is  a  matter  of  common  knowledge  that  the  work  of  prison  reform 
in  England  at  the  time  of  which  we  write  was  due  largely  to  the  efforts 
of  John  Howard  and  his  work  was  begun  in  1773. 

While  the  great  land  owners  accumulated  wealth,  the  poacher  who 
snared  a  rabbit  was  sent  to  jail  or  deported.  The  condition  of  the  poor 
was  hopeless  and  the  best  blood  of  England  flowed  willingly  or  unwill- 
ingly into  the  United  States,  Canada  and  Australia.  However,  typhus 
often  pursued  the  poor  emigrant  in  his  flight  by  sea  and  it  is  said  that 
one-third  the  immigrants  to  America  in  the  eighteenth  century  died 
during  or  soon  after  the  voyage.  It  is  well  known  that  the  fatality 
from  ship  fever  continued  through  the  early  part  of  the  nineteenth 
century.  During  the  American  War  (1774-1780)  the  number  of 
British  seamen  raised  was  175,990,  the  number  of  those  who  died  of 
disease  was  18,545,  and  the  number  killed  was  1,243. 

It  is  interesting  to  'note  that  during  the  eighteenth  century  English 
physicians  for  the  most  part  were  not  much  concerned  with  the  poor 
and  many  of  them  saw  but  little  typhus,  while  a  colleague  busy  among 
the  poor  saw  much  of  it.  A  Dr.  Moss,  writing  of  diseases  in  Liver- 
pool, said  that  typhus  was  rare  at  a  time  when  Dr.  Currie  was  seeing 
more  than  3,000  cases  a  year.  In  1790  Liverpool  was  the  second  city 
in  England  with  a  population  of  56,000,  while  that  of  London  was 
estimated  at  800,000.  According  to  Currie  7,000  of  the  people  of 
Liverpool  lived  in  cellars  and  9,000  more  in  back  houses  with  small 
courts  and  with  narrow  passages  to  the  streets.  In  ten  years  (1787- 
1796)  31,243  cases  of  fever  were  registered,  an  average  of  3,124  per 
year.  In  the  last  quarter  of  the  eighteenth  century  Chester  was 


102  TYPHUS    FEVER 

regarded  as  the  most  desirable  residence  city  in  the  kingdom.  Within 
the  walls,  it  had  a  population  of  about  3,500  and  from  1764-1773  the 
death  rate  was  only  17.2  per  1,000,  but  the  poor  lived  outside  the  walls 
and  Haygarth  describes  the  condition  as  follows : 

The  houses  were  small,  close,  crowded  and  dirty,  ill  supplied  with  water, 
undrained,  and  built  on  ground  that  received  the  sewage  from  within  the 
walls.  The  people  were  ill-fed  and  they  seldom  changed  or  washed  their 
clothes;  when  they  went  abroad  they  were  noisome  and  offensive  to  the  smell. 
...  In  these  poor  habitations  when  one  person  was  seized  with  the  fever, 
others  of  the  same  family  are  generally  affected  with  the  same  fever  in  a 
greater  or  lesser  degree. 

The  second  half  of  the  eighteenth  century  saw  the  great  manu- 
facturing development  of  England  by  the  employment  of  machinery. 
Now  the  poor  were  exploited  by  the  manufacturer.  The  houses  occu- 
pied by  the  operatives  are  said  by  Ferrier  to  have  been  dirty,  without 
ventilation,  and  with  the  beds  almost  touching.  "As  soon  as  one  poor 
creature  dies  or  is  driven  out  of  his  cell,  he  is  replaced  by  another, 
generally  from  the  country,  who  soon  feels  in  his  turn  the  conse- 
quences of  breathing  infected  air."  The  only  voices  heard  in  behalf 
of  the  poor  were  those  of  medical  men,  and  in  Manchester  Ferrier 
pleaded  for  them  in  strong  language : 

I  have  seen  patients  in  agonies  of  despair  on  finding  themselves  over- 
whelmed with  filth  and  abandoned  by  everyone  who  could  do  them  any  service. 
.  .  .  The  situation  of  the  poor  at  present  is  extremely  dangerous,  and  often 
destructive  to  the  middle  and  higher  ranks  of  society.  .  .  .  The  poor  are 
indeed  the  first  sufferers,  but  the  mischief  does  not  always  rest  with  them.  By 
secret  avenues  it  reaches  the  most  opulent  and  severely  revenges  their  neglect 
or  insensibility  to  the  wretchedness  surrounding  them. 

It  was  the  fact  that  typhus  occasionally  found  its  way  into  the 
midst  of  the  rich,  and,  when  it  did,  killed  so  many  and  so  quickly, 
that  they  were  compelled  to  recognize  that  the  misfortunes  of  the  poor 
were  of  concern  to  themselves.  Finally  in  a  half-hearted  way,  urged 
by  physicians,  growling  about  the  wastefulness  and  improvidence  of 
the  laboring  classes,  driven  by  the  occasional  deadly  outbreaks  in  their 
own  ranks,  the  ruling  classes  began  to  provide  special  hospitals  for  the 
isolation  and  care  of  cases  of  typhus.  The  London  fever  hospital 
was  established  in  1802. 


TYPHUS    FEVER  103 

The  epidemiologic  history  of  Britain  during  the  Napoleonic  wars 
presents  many  points  of  interest.  Food  prices  were  high.  For  a  time 
American  markets  were  closed  to  British  manufacturers.  Still,  the 
period  (1803-1816)  was  comparatively  free  from  typhus,  so  far  as 
Britain  was  concerned.  In  peace  the  poor  man's  business  is  to  serve 
the  rich,  clothe  himself  in  rags,  rear  his  family  in  a  stye  and  eat 
nothing.  In  war  he  becomes  a  hero,  the  defender  of  his  king  and 
country.  He  is  well  clothed,  well  fed  and  all  that  is  asked  of  him  is 
that  he  die  for  his  country  if  need  be.  The  wife  and  children  at 
home  must  be  cared  for  because  more  soldiers  will  be  needed. 

Immediately  after  the  declaration  of  peace  (1816)  typhus  began  to 
increase  and  within  another  year  it  took  on  epidemic  proportions. 
The  condition  of  the  London  slums  of  the  time  is  shown  by  a  Par- 
liament report  as  quoted  by  Creighton: 

Calmel's  Buildings,  a  small  court  near  Portman  Square,  consisting  of  twenty- 
four  houses,  in  which  lived  seven  hundred  Irish  in  distress  and  profligacy,  neg- 
lected by  the  parish  and  shunned  by  everyone  from  fear  of  contagion.  George 
Yard,  Whitechapel,  consisting  of  forty  houses  in  which  lived  two  thousand 
persons  in  a  similar  state  of  wretchedness. 

In  1831  typhus  became  epidemic  in  England  and  continued  its  rav- 
ages for  more  than  ten  years.  The  destitution  and  sickness  among 
the  poor  of  Manchester  in  the  latter  part  of  this  epidemic  (1839-1841) 
formed  the  basis  of  the  story  of  Mary  Barton  written  by  Mrs.  Gaskell. 
The  author  dwells  on  the  bitterness  on  the  part  of  the  poor. 

The  most  deplorable  and  enduring  evil  that  arose  out  of  the  period  of  com- 
mercial depression  to  which  I  refer,  was  this  feeling  of  alienation  between  the 
different  classes  of  society.  It  is  so  impossible  to  describe,  or  even  faintly  to 
picture,  the  state  of  distress  which  prevailed  in  the  town  at  that  time,  that  I 
will  not  attempt  it;  yet  I  think  again  that  surely  in  a  Christian  land,  it 
was  not  known  so  feebly  as  words  could  tell  it,  or  the  more  fortunate  and 
happy  would  have  thronged  with  their  sympathy  and  aid.  In  many  instances 
the  sufferers  wept  first  and  then  cursed.  Their  vindictive  feelings  exhibited 
themselves  in  rabid  politics.  And  when  I  hear,  as  I  have  heard,  of  the  suffer- 
ings and  privations  of  the  poor,  of  provision  shops  where  ha'porths  of  tea, 
sugar,  butter  and  even  flour  were  sold  to  accommodate  the  indigent  —  of  parents 
sitting  in  their  clothes  by  the  fireside  during  the  whole  night  for  seven  weeks 
together,  in  order  that  their  only  bed  and  bedding  might  be  reserved  for  the 
use  of  their  large  family  —  of  others  sleeping  upon  the  cold  hearth  stone  for 


104  TYPHUS    FEVER 

weeks  in  succession  without  adequate  means  of  providing  themselves  with 
food  or  fuel  —  and  this  in  the  depth  of  winter  —  of  others  being  compelled 
to  fast  for  days  together,  uncheered  by  any  hope  of  better  fortune,  living,  more- 
over, or  rather  starving  in  a  crowded  garret  or  damp  cellar,  and  gradually 
sinking  under  the  pressure  of  want  and  despair  into  a  premature  grave;  and 
when  this  has  been  confirmed  by  the  evidence  of  their  careworn  looks,  their 
excited  feelings,  and  their  desolated  homes  —  can  I  wonder  that  many  of  them, 
in  such  times  of  misery,  and  destitution,  spoke  and  acted  with  ferocious  pre- 
cipitation ? 

In  1847-1848  there  was  a  revival  of  typhus,  under  the  name  of 
"Irish  Fever,"  in  England.  The  last  epidemic  in  England  occurred 
in  1863-1864,  and  was  in  part  due  to  the  "cotton  famine"  resulting 
from  the  Civil  war  in  our  own  country.  Since  that  time  typhus  has 
gradually  decreased  in  Britain,  but  has  not  entirely  disappeared. 

From  the  fact  that  I  have  dwelt  on  typhus  in  Britain,  it  must  not 
be  inferred  that  it  was  unknown  or  was  less  prevalent  on  the  conti- 
nent of  Europe  during  the  seventeeth,  eighteenth  and  nineteenth  cen- 
turies. It  was  constantly  present  and  assumed  epidemic  proportions 
of  varying  intensity  in  diverse  places  at  different  times.  No  European 
nation  has  been  wholly  free  from  it  and  it  has  continued  to  develop 
epidemics  especially  in  Austria  and  Russia.  The  present  war  has 
developed  the  conditions  most  favorable  to  its  dissemination  and  I 
shall  not  attempt  to  predict  the  part  it  may  play  in  the  savage  struggle 
now  going  on. 

Taking  Europe  as  a  whole  the  period  from  about  1670  to  about 
1850  may  be  considered  as  the  typhus  age.  This  does  not  mean  that 
this  disease  did  not  exist  before  this  period  or  that  it  ceased  with  the 
close  of  it.  Neither  assumption  would  be  true,  but  before  that  time 
typhus  was  overshadowed  for  many  centuries  by  the  more  deadly 
plague.  Still  it  is  a  question  if  even  at  that  time  typhus  did  not  kill 
more  than  the  plague.  The  former  was  constantly  present  while  the 
latter  lapsed  from  time  to  time  apparently  on  account  of  lack  of 
susceptible  material.  Even  during  the  typhus  age  other  deadly  infec- 
tions, as  smallpox,  tuberculosis,  diphtheria,  etc.,  aided  in  rolling  up 
heavy  mortality  lists.  A  complete  history  of  typhus  would  be  a  valu- 
able contribution  to  human  knowledge  and  should  be  studied  by  states- 
men and  all  interested  in  the  welfare  of  the  race,  as  well  as  physicians. 


TYPHUS    FEVER  105 

There  is  certainly  one  great  lesson  which  it  teaches  and  that  is  that 
the  health  conditions  of  the  poor  are  of  interest  to  all.  No  nation  can 
be  great  so  long  as  its  laboring  classes  live  under  unhygienic  condi- 
tions. Typhus  impoverished  Europe  not  only  by  its  high  mortality  but 
by  the  great  emigration  from  its  shores,  leaving  the  degenerate  to 
beget  its  generations. 

Before  leaving  the  history  of  typhus  in  Europe,  I  wish  to  quote  the 
definition  of  the  disease  given  by  the  greatest  English  authority  of  the 
nineteenth  century,  Murchison: 

A  disease  attacking  persons  of  all  ages  generated  by  contagion,  or  by  over- 
crowding of  human  beings,  with  deficient  ventilation,  and  prevailing  in  epidemic 
form,  in  periods  or  under  circumstances  of  famine  and  destitution.  Its  symp- 
toms are :  more  or  less  sudden  invasion  marked  by  rigors  or  chilliness ;  fre- 
quent, compressible  pulse;  tongue  furred  and  ultimately  dry  and  brown; 
bowels,  in  most  cases,  constipated ;  skin  warm  and  dry ;  a  rubeoloid  rash  appear- 
ing between  the  fourth  and  seventh  days,  the  spots  never  appearing  in 
successive  crops,  at  first  slightly  elevated,  and  disappearing  on  pressure, 
but,  after  the  second  day,  persistent,  and  often  becoming  converted  into  true 
petechiae ;  great  and  early  prostration;  heavy  flushed  countenance;  injected 
conjunctivae;  watchfulness  and  obtuseness  of  the  mental  faculties,  followed 
at  the  end  of  the  first  week  by  delirium,  which  is  sometimes  acute  and  noisy, 
but  oftener  low  and  wandering;  tendency  to  stupor  and  coma,  tremors,  sub- 
sultus,  and  involuntary  evacuations,  with  contracted  pupils.  Duration  of  the 
fever  from  ten  to  twenty-one  days,  usually  fourteen.  In  the  dead  body  no  spe- 
cific lesion;  but  hyperemia  of  all  the  internal  organs,  softening  of  the  heart, 
hypostatic  congestion  of  the  lungs,  atrophy  of  the  brain,  and  edema  of  the 
pia  mater  are  common. 

Typhus  fever  became  epidemic  in  Mexico  soon  after  the  conquest 
(1530)  and  has  continued  in  endemic  form  with  occasional  severe 
exacerbations  to  the  present  time.  According  to  Liceaga  the  second 
recorded  epidemic  occurred  in  1545  and  the  third  in  1575.  In  1736- 
1737  the  disease  is  said  to  have  killed  192,000.  During  the  nineteenth 
century  there  were  many  exacerbations,  the  most  extensive  of  which 
was  in  1861.  At  the  present  time  typhus  is  common  in  Mexico. 

Importations  of  typhus  by  immigrants  into  this  country  have  been 
constant  and  it  is  probable  that  at  no  time  have  our  large  cities  been 
wholly  free  from  it,  but  in  most  instances  it  has  been  limited  to 
recently  arrived  immigrants  and  those  directly  in  contact  with  them. 


106  TYPHUS    FEVER 

Doty  says:  "Out  of  439  cases  of  typhus  fever  which  occurred  in 
New  York  during  1892-1893,  434  were  removed  from  the  poorer 
tenement  and  lodging  houses,  principally  the  latter." 

In  the  records  of  the  civil  war  1,723  cases  with  572  deaths  are 
reported  under  this  name,  but  the  diagnosis  of  many  of  these  were 
questioned  by  the  best  medical  officers,  such  as  Woodward  and  Clymer. 
No  cases  were  reported  by  Confederate  officers.  It  is  certain  that 
typhus  did  not  play  any  marked  part  in  the  mortality  of  that  war. 

THE   TRANSMISSION   OF   TYPHUS 

In  1909  Nicolle,  stationed  in  Algiers,  made  two  notable  discoveries 
concerning  the  transmission  of  typhus  fever.  In  the  first  place,  he 
induced  the  disease  in  the  chimpanzee  by  injecting  the  blood  of  patients 
and  in  like  manner  he  transferred  the  disease  from  the  chimpanzee 
to  the  macacus  monkey.  He  was  not  able  to  transfer  the  disease  in 
this  way  directly  from  man  to  monkey,  but  could  do  so  indirectly 
through  the  chimpanzee.  This  suggests  that  the  virus  is  increased  in 
intensity  by  passage  through  the  chimpanzee.  In  the  second  place, 
Nicolle  succeeded  in  transmitting  typhus  from  monkey  to  monkey 
by  the  bite  of  the  body  louse.  Typical  eruptions  were  secured  in  the 
chimpanzee  constantly,  but  not  uniformly  in  the  monkey. 

The  fact  that  typhus  is  transferable  by  the  bite  of  the  body  louse 
has  been  confirmed  by  Anderson  and  Goldberger,  Ricketts  and  others. 
This  renders  it  desirable  for  us  to  know  as  much  as  possible  con- 
cerning the  life  history  of  this  parasite.  Shipley  of  Cambridge,  Eng- 
land, has  recently  made  studies  along  this  line  and  I  follow  him 
principally  in  the  following  statements :  The  body  louse  ( Pediculis 
vestimenti)  is  somewhat  larger  than  the  head  louse  and  carries  longer 
antennae.  The  male  is  about  3  mm.  long  and  1  mm.  broad.  The  female 
is  about  one-tenth  larger.  Its  color  is  said  to  vary  with  that  of  the 
people  on  whom  it  feeds,  black,  brown,  and  with  different  shades  of 
grayish  white.  It  does  not  move  about  over  the  surface  but  is  always 
attached  to  the  inner  side  of  the  underclothing.  Even  in  feeding,  it 
remains  attached  by  at  least  one  of  its  six  legs  to  the  clothing.  When 
a  lousy  person  is  stripped,  no  lice  can  be  found  on  him,  but  the  inner 
side  of  the  underclothing  may  be  alive  with  them.  When  grown  for 
the  purpose  of  study,  they  must  be  permitted  to  attach  themselves  to 


TYPHUS    FEVER  107 

bits  of  flannel  and  these  must  be  brought  into  contact  with  the  skin 
and  the  lice  allowed  to  eat  twice  a  day.  They  take  hold  promptly  and 
feed  greedily  but  never  detach  themselves  from  the  flannel.  The 
female  after  pairing  begins  to  deposit  eggs  or  nits  at  the  rate  of  about 
5  per  day.  These  hatch  after  periods  which  vary  markedly  with 
the  temperature.  Cold  delays  the  hatching,  but  even  freezing  does  not 
destroy  the  nits.  Under  favorable  conditions  the  larvae  emerge  about 
the  sixth  day,  and  immediately  begin  to  feed.  Body  lice  seem  not 
to  be  hardy  and  soon  die  unless  they  have  frequent  opportunity  of 
feeding,  but  the  clothing  may  carry  the  nits  quite  indefinitely  and 
these  may  hatch  when  the  conditions  become  favorable.  The  newly 
hatched  do  not  survive  more  than  thirty-six  hours  without  food. 
The  lice  are  easily  killed  by  gasoline  or  benzine  or  by  turning  the 
underclothing  inside  out  and  carefully  applying  a  hot  iron.  Special 
attention  should  be  given  to  the  seams.  Boiling  quickly  destroys 
both  the  insects  and  their  eggs.  It  will  be  seen  that  as  simple  as 
these  requirements  are  in  ordinary  life  they  are  quite  impracticable 
to  the  soldier  in  the  trenches,  especially  when  he  has  no  change  of 
underclothing.  It  is  said  that  this  parasite  feeds  only  on  dirty  people 
and  that  it  will  not  Infest  those  who  wear  silk,  but  the  soldier  must 
be  dirty,  sometimes  at  least,  and  he  is  not  supplied  with  silk  under- 
wear. Gasoline  and  benzine  cannot  be  used  by  the  soldier  on  account 
of  their  ready  inflammability.  A  dilute  solution  of  lysol  or  cresol 
soap  made  into  a  lather  is  applied  to  the  inside  of  the  clothing  and 
left  there  to  dry.  Physicians  and  nurses  in  caring  for  typhus  patients 
are  exposed  to  great  danger  and  the  death-rate  among  them  has 
always  been  high.  In  recent  years  more  than  one  medical  man  has 
contracted  typhus  in  trying  to  solve  its  etiology  and  of  the  six  Ameri- 
can physicians  who  have  recently  studied  typhus  fever  in  Mexico 
three  have  contracted  the  disease  and  two  have  died — Conneff  of  the 
State  University  of  Ohio  and  Ricketts  of  the  University  of  Chicago. 
These  are  names  now  added  to  the  martyr  roll  of  science.  Of 
Ricketts,  his  teacher  and  friend,  Hektoen,  has  deservingly  said: 

Those  near  him  know  that  he  fully  understood  the  dangers  to  which  he 
would  be  exposed  and  the  risks  he  would  run.  He  decided  he  would  take  those 
risks,  meet  the  dangers  with  all  possible  means  of  prevention,  and  do  the  work 
that  would  come  to  his  hands.  And  so  he  made  the  great  sacrifice  and  gave 
all  that  a  man  can  give  to  his  fellow  men. 


108  TYPHUS    FEVER 

Other  American  medical  men  and  nurses  have  given  their  lives  in 
the  combat  with  this  disease  in  desolated  Serbia  and  others  still  are 
there  and  elsewhere  in  war-scourged  Europe,  seeking  not  to  destroy 
but  to  save  lives,  fighting  under  the  great  battle  flag  of  humanity  and 
science. 

Quite  independently  of  the  work  of  Nicolle,  Anderson  and  Gold- 
berger,  Ricketts  and  Wilder,  Conner!  and  others  studied  the  etiology 
of  typhus  in  Mexico.  They  found  that  the  disease  could  be  trans- 
mitted from  man  to  the  lower  monkeys,  without  passage  through  a 
chimpanzee,  that  the  virus  in  the  blood  is  removed  by  nitration  through 
porcelain,  that  one  attack  in  the  monkey  gives  immunity  and  that 
Nicolle  was  right  in  his  claim  that  the  disease  is  transmitted  by  the 
body  louse.  All  attempts  to  transfer  the  disease  by  fleas  and  bed  bugs 
have  failed,  while  those  with  the  head  louse  (Pediculis  capitis)  have 
not  given  uniform  results. 

For  some  years  Brill  has  observed  a  peculiar  disease  in  the  wards 
of  Mount  Sinai  Hospital,  New  York,  and  up  to  the  present  time  he 
has  records  of  about  three  hundred  cases.  Brill  has  described  this 
disease  as  follows: 

An  acute  infectious  disease  of  unknown  origin  and  unknown  pathology, 
characterized  by  an  incubation  period  of  from  four  to  five  days,  a  period  of 
continuous  fever,  accompanied  by  intense  headache,  apathy,  and  prostration,  a 
profuse  and  extensive  erythematous  maculo-papular  eruption,  all  of  about  two 
weeks  duration,  whereupon  the  fever  abruptly  ceases  either  by  crisis  within 
a  few  hours  or  by  rapid  lysis  within  three  days. 

Anderson  and  Goldberger  have  shown  that  Brill's  disease  is  typhus 
fever  by  injecting  the  blood  of  patients  into  monkeys  and  thereby 
establishing  immunity  to  typhus. 

Nicolle  has  reduced  typhus  in  Tunis  from  838  cases  in  1909  to  22 
cases  in  1912.  The  only  measure  employed  consists  in  freeing  the 
people  of  lice. 

THE  ORGANISM 

Plotz  has  isolated  the  organism  and  with  Olitsky  and  Baeher  has 
shown  by  complement  fixation  and  agglutination  tests  that  he  has, 
most  probably,  found  the  infecting  agent.  In  the  agglutination  tests 
only  positive  reactions  in  dilutions  1 :  50  were  considered. 


TYPHUS    FEVER  109 

Of  twenty-four  cases  tested  before  the  crisis  all  were  negative  except  two 
which  were  tested  one  day  before  the  crisis,  both  of  which  had  a  titre  of  1 : 100. 
Of  ten  cases  tested  on  the  day  of  the  crisis,  three  were  positive  and  seven  nega- 
tive. After  the  crisis,  thirty-eight  cases  were  studied,  92.6  per  cent,  of  which 
were  positive.  Agglutinins  have  been  demonstrated  as  late  as  five  months 
after  the  crisis.  Of  a  very  large  series  of  control  cases,  no  case  gave  a  reac- 
tion in  a  dilution  above  1 :  50,  except  three  cases  in  which  the  occurrence  of 
a  previous  attack  of  typhus  fever  could  not  be  excluded.  In  these  cases  the 
reactions  varied  from  1 :100  to  1 : 200.  Control  studies  made  by  testing  the 
serum  of  typhus  cases  against  various  other  organisms  were  negative. 

The  opsonic  index  increases  at  the  crisis  and  remains  high  in  the 
convalescent  stage. 

The  organism  is  a  small  gram-positive  bacillus,  from  0.9  to  1.93  microns 
in  length,  the  breadth  being  from  one-fifth  to  three-fifths  of  the  length.  It  is 
not  acid-fast,  has  no  capsule,  and  polar  bodies  can  be  demonstrated  by  appro- 
priate methods.  When  first  isolated,  it  grows  only  anaerobically,  but  after  a 
time  it  can  be  grown  aerobically. 

Intraperitoneal  inoculation  of  a  pure  culture  of  the  organism  into  guinea- 
pigs  produces  a  rise  of  temperature  in  from  twenty-four  to  forty-eight  hours, 
the  temperature  remaining  high  for  four  or  five  days,  and  then  dropping  by 
crisis.  This  corresponds  to  the  reaction  seen  in  guinea-pigs  after  inoculation 
with  defibrinated  blood  from  typhus  fever  patients,  except  that  the  incubation 
period  is  shorter.  Serum  from  a  convalescing  typhus  patient  has  bactericidal 
properties  against  the  organism  obtained  from  Brill's  disease  and  typhus  fever. 


CHAPTER    XII 


THE    PLAGUE 

History. — According  to  Sticker  the  history  of  this  disease  can  be 
traced  back  to  the  time  of  the  exodus  of  the  Children  of  Israel  from 
Egypt.  The  Egyptians  of  the  Pharaohs  drained  the  land,  built  aque- 
ducts, disposed  of  their  dead  hygienically,  reared  temples,  maintained 
law  and  order,  developed  the  elements  of  literature  and  science  and 
devised  and  employed  simple  machinery.  In  speaking  of  the  ancient 
Egyptians,  Diodorus  says,  "The  whole  manner  of  life  was  so  evenly 
ordered  that  it  would  appear  as  though  it  had  been  arranged  by  a 
learned  physician  rather  than  by  a  lawgiver."  Herodotus  declared 
ancient  Egypt  the  healthiest  of  countries,  but  filled  with  physicians, 
of  whom  "one  treats  only  the  diseases  of  the  eye,  another  those  of 
the  head,  the  teeth,  the  abdomen,  or  the  internal  organs."  Writing  of 
a  later  time,  Gibbon  said  "Ethiopia  and  Egypt  have  been  stigmatized 
in  all  ages  as  the  source  and  seminary  of  the  plague."  It  is  evident 
that  in  the  time  of  its  great  civilization  Egypt  was  salubrious ;  coinci- 
dent with  the  decline  in  the  learning  and  wisdom  of  its  people,  it  was 
visited  and  desolated  by  pestilence.  That  Egypt  had  lost  its  salubrity 
as  early  as  the  exodus  of  the  Children  of  Israel  is  shown  by  many  pas- 
sages in  the  Bible  in  which  the  chosen  people  are  threatened  with  the 
diseases  of  Egypt  if  they  neglect  or  violate  the  laws.  Moses,  "learned 
in  all  the  wisdom  of  the  Egyptians"  codified  his  sanitary  rules  and 
regulations  in  the  form  of  religious  rites  and  ceremonies  and  thus 
secured  their  observance  among  the  faithful,  even  down  to  the  present 
time. 

Sticker  is  quite  confident  that  the  pest  among  the  Philistines 
spoken  of  in  the  first  book  of  Samuel,  when  the  captured  ark  was 
returned  with  five  golden  emerods  and  five  golden  mice,  was  the 
bubonic  plague. 

Of  the  true  nature  of  the  Athenian  plague  described  by  Thucydides 
there  is  some  doubt.  It  is  generally  believed  to  have  been  the  plague, 
but  the  description  is  not  sufficiently  clear  to  justify  a  positive  con- 


112  THE    PLAGUE 

elusion.  It  has  been  suggested  that  it  might  have  been  typhus  fever, 
but  I  think  that  the  greatest  probability  is  in  favor  of  its  having  been 
the  pneumonic  form  of  the  plague. 

The  time  of  the  earliest  appearance  of  the  plague  in  Italy  is  not 
known.  It  was  certainly  quite  well  established  there  in  the  first  cen- 
tury of  the  Christian  era  and  in  all  probability  this  was  not  the  first 
visitation.  The  historian,  as  a  rule,  confines  his  descriptions  to  martial 
and  political  events  and  consequently  gives  a  wholly  erroneous  idea 
of  true  conditions.  Gibbon  says:  "If  a  man  were  called  upon  to  fix 
the  period  in  the  history  of  the  world,  during  which  the  condition  of 
the  human  race  was  most  happy  and  prosperous,  he  would  without 
hesitation,  name  that  which  elapsed  from  the  death  of  Domitian  to 
the  accession  of  Commodus"  (from  96  to  180  A.  D.).  Noah  Webster, 
in  his  work  on  epidemics  and  pestilence,  quotes  the  preceding  with  the 
following  just  comment: 

It  is  certain  that,  at  this  time,  the  Roman  Empire  was  in  its  glory,  and 
governed  by  a  series  of  able  and  virtuous  princes,  who  made  the  happiness  of 
their  subjects  their  principal  object.  But  the  coloring  given  to  the  happiness 
of  this  period  is  far  too  brilliant.  The  success  of  armies  and  the  extent  of 
empire  do  not  constitute  exclusively  the  happiness  of  nations;  and  no  historian 
has  a  title  to  the  character  of  fidelity,  who  does  not  comprehend,  in  his  general 
description  of  the  state  of  mankind,  moral  and  physical,  as  well  as  political 
evils. 

Let  us  make  brief  inquiry  into  the  diseases  of  this  "most  happy 
and  prosperous"  period.  It  was  preceded  by,  it  begun  in,  continued  in, 
and  closed  in  pestilence.  That  the  plague  was  endemic  in  Italy  at  that 
time  and  that  it  developed  in  epidemic  form  with  each  increase  in  sus- 
ceptible material  there  can  be  no  doubt.  Of  the  epidemic  of  68  A.  D. 
Tacitus  says : 

Houses  were  filled  with  dead  bodies  and  the  streets  with  funerals;  neither 
age  nor  sex  were  exempt;  slaves  and  plebians  were  suddenly  taken  off,  amidst 
the  lamentations  of  their  wives  and  children,  who,  while  they  assisted  the  sick, 
or  mourned  the  dead,  were  seized  with  the  disease,  and  perishing,  were  burned 
on  the  same  funeral  pyre.  To  the  knights  and  senators  the  disease  was  less 
mortal,  though  these  also  suffered  in  the  common  calamity. 

About  this  time  the  plague  appears  to  have  spread  over  the  whole 
of  Asia,  northern  Africa  and  Europe.  According  to  Short,  the  deaths 


THE    PLAGUE  113 

from  this  disease  in  Scotland  between  88  and  92  A.  D.  amounted  to 
not  less  than  150,000.  This  was  probably  not  less  than  one-fourth, 
possibly  one-half,  the  population  of  Scotland  at  that  time. 

In  the  year  80  A.  D.  the  deaths  from  the  plague  in  Rome  at  the 
height  of  the  epidemic  numbered  10,000  a  day.  It  is  estimated  that  the 
population  of  Rome  at  that  time  was  somewhat  more  than  one  million. 
Rufus  of  Ephesus,  who  lived  in  the  reign  of  Trajan  (98-117  A.  D.) 
has  left  a  description  of  the  epidemic  of  his  time  which  leaves  no 
doubt  about  its  being  the  plague.  "Pestilentes  bubones,  maxime  letales 
et  acuti,  qui  maxime  circa  Lybiam,  et  Aegyptum  et  Syriam  obser- 
vantur." 

Exacerbations  of  the  disease  in  Rome  are  recorded  for  the  years 
102,  107  and  117  A.  D.  According  to  Short,  45,000  died  of  the  plague 
in  Wales  in  114  A.  D.  The  year  167  A.  D.  is  noted  for  an  unusually 
severe  outbreak  of  the  plague  at  Rome,  where  it  continued  for  many 
years.  In  the  year  173  A.  D.,  the  Roman  army  was  threatened 'with 
extinction  by  disease,  and  special  epidemics,  or  rather  exacerbations 
of  the  epidemic,  prevailed  in  Rome  in  175  and  178  A.  D.  That  the 
"happy  and  prosperous"  period  was  followed  by  a  continuation  of  the 
plague  is  shown  by  the  following  quotation  from  Herodian : 

A  great  pestilence  raged  throughout  Italy  at  that  time  (about  187  A.  D.)  but 
with  most  violence  in  the  city,  by  reason  of  the  great  concourse  of  people  assem- 
bled from  all  parts  of  the  earth.  The  mortality  among  men  and  cattle  was 
great.  The  emperor,  by  advice  of  physicians,  retired  to  Laurentium,  on  account 
of  the  coolness  of  the  place,  which  was  shaded  with  laurels.  It  was  supposed 
that  the  fragrance  of  the  laurels  acted  as  an  antidote  against  the  contagion. 
The  people  in  the  city  also,  by  the  advice  of  physicians,  filled  their  noses  and 
ears  with  sweet  ointments  and  used  perfumes,  etc. 

Under  the  spell  of  the  historian  we  have  been  inclined  to  regard 
the  period  when  the  great  philosopher,  Marcus  Aurelius  Antoninus, 
sat  on  the  throne  of  the  world,  as  the  golden  age.  Let  us  therefore 
listen  to  a  few  words  from  his  personal  attendant,  courtier  and  his- 
torian, who  writes: 

Unless  he,  M.  Antoninus,  had  been  born  at  this  juncture,  the  affairs  of  the 
empire  would  have  fallen  into  speedy  ruin,  for  there  was  no  respite  from  mili- 
tary operations.  War  raged  in  the  east,  in  Illyricum,  in  Italy  and  in  Gaul. 
Earthquakes  with  the  destruction  of  cities,  inundations  of  rivers,  frequent 


114  THE    PLAGUE 

plagues,  a  species  of  locusts  ravaging  the  fields;  in  short,  every  calamity  that 
can  be  conceived  to  afflict  and  torment  man  scourged  the  human  race  during 
his  administration. 

The  physician  and  historian,  Procopius,  in  his  account  of  the  great 
pestilence  in  the  reign  of  Justinian  "emulated  the  skill  and  diligence 
of  Thucydides  in  the  description  of  the  plague  at  Athens."  Of  this 
epidemic  Gibbon  says: 

In  time  its  first  malignancy  was  abated  and  dispersed;  the  disease  alternately 
languished  and  revived;  but  it  was  not  till  the  end  of  a  calamitous  period  of 
fifty-two  years,  that  mankind  recovered  their  health,  and  the  air  resumed  its 
pure  and  salubrious  quality.  No  facts  have  been  preserved  to  sustain  an  account, 
or  even  a  conjecture,  of  the  numbers  that  perished  in  this  extraordinary  mor- 
tality. I  only  find  that  during  three  months,  four  and  at  length  ten  thousand 
persons  died  each  day  at  Constantinople,  that  many  cities  of  the  east  were  left 
vacant,  and  that  in  several  districts  of  Italy,  the  harvest  and  the  vintage  withered 
on  the  ground.  The  triple  scourge  of  war,  pestilence  and  famine  afflicted  the 
subjects  of  Justinian,  and  his  reign  is  disgraced  by  a  visible  decrease  of  the 
human  species,  which  has  never  been  replaced  in  some  of  the  fairest  countries 
of  the  globe. 

This  epidemic  spread  over  the  whole  of  Europe  and  it  took  more 
than  a  century  to  reach  England,  where  "it  fabled  long  after  in  prose 
and  verse  as  the  great  plague  of  Cadwalader's  time."  Then  for  quite 
a  thousand  years  it  reaped  its  periodic  harvests  as  often  as  immunity 
was  lost  in  new  generations. 

In  the  fourth  century  the  seat  of  government  was  removed  to 
Byzantium.  It  is  probable  that  this  change  was,  in  part  at  least, 
determined  by  the  insalubrity  of  Italy.  Early  in  the  fifth  century 
Rome  was  pillaged,  but  the  real  conquerors  of  Rome  were  not  the 
Goths  and  Vandals,  but  malaria  and  the  plague.  Disease  continued 
to  devastate  Italy.  Creighton  says : 

About  the  year  668  the  English  archbishop-elect,  Vighard,  having  come  to 
Rome  to  get  his  election  confirmed  by  the  pope,  Vitalanius,  was  soon  after  his 
arrival  cut  off  by  the  pestilence  with  almost  all  who  had  gone  with  him.  Twelve 
years  after,  in  680,  there  was  another  severe  pestilence  in  the  months  of  July, 
August  and  September,  causing  a  great  mortality  at  Rome  and  such  a  panic 
at  Pavia  that  the  inhabitants  fled  to  the  mountains.  In  746  a  pestilence  is  said 
to  have  advanced  from  Sicily  and  Calabria  and  to  have  made  such  devastation 
in  Rome  that  there  were  houses  without  a  single  inhabitant  left. 


THE    PLAGUE  115 

From  that  time  on  the  plague  periodically  spread  over  Italy  until 
the  seventeenth  century,  while  malaria  has  been  in  continuous  posses- 
sion down  to  our  own  time.  We  are  told  that  the  epidemic  of  1348 
reduced  the  inhabitants  of  the  Eternal  City  to  20,000. 

We  are  familiar  with  the  graphic  description  of  the  plague  in 
Florence  by  Bocaccio,  who  wrote: 

Such  was  the  cruelty  of  Heaven  and  perhaps  of  men,  that  between  March 
and  July  following,  it  is  supposed,  and  made  pretty  certain,  that  upwards  of 
a  hundred  thousand  souls  perished  in  the  city  only,  whereas,  before  that  calam- 
ity, it  was  not  supposed  to  have  contained  so  many  inhabitants.  What  mag- 
nificent dwellings,  what  noble  palaces  were  then  depopulated  to  the  last  person, 
what  families  extinct,  what  riches  and  vast  possessions  left,  and  no  known  heir 
to  inherit,  what  numbers  of  both  sexes  in  the  prime  and  vigor  of  youth  —  whom 
in  the  morning  neither  Galen,  Hippocrates  nor  Esculapius  himself,  but  would 
have  declared  in  perfect  health  —  after  dining  heartily  with  their  friends  here, 
have  supped  with  their  departed  friends  in  the  other  world. 

It  is  worthy  of  note  that  Guy  de  Chauliac,  body  physician  to 
Clement  VI  (pope  from  1342  to  1352)  recognized  the  two  forms  of 
the  plague.  He  wrote : 

Pestis  habuit  duos  modos.  Primus  fuit  per  duos  menses  cum  febre  continua 
et  sputo  sanguinis.  Et  isti  moriebantur  infra  tres  dies.  Secundus  fuit  per 
residuum  temporis  cum  febre  etiam  continua  et  apostematibus  et  anthracibus 
in  exterioribus,  potissime  in  subaxellis  et  inguinibus.  Et  moriebantur  infra 
quinque  dies.  Et  fuit  tantae  contagiositatis,  specialiter  quae  fuit  cum  sputo 
sanguinis,  quod  non  solum  morando,  sed  etiam  inspiciendo  unus  recipiebat  ab 
alio. 

There  are  but  few  passages  in  literature  so  tragic  as  the  short 
record  of  the  plague  of  the  fourteenth  century  begun  by  the  friar  of 
Kilkenny,  but  soon  interrupted  by  his  death : 

I  friar,  John  Clyn,  of  the  order  of  Friars  Minor  and  of  the  convent  of  Kil- 
kenny, wrote  in  this  book  those  notable  things  which  happened  in  my  times, 
which  I  saw  with  my  eyes,  or  which  I  learned  from  persons  worthy  of  credit. 
And  lest  these  things  worthy  of  remembrance  should  perish  with  time  and  fall 
away  from  the  memory  of  those  who  are  to  come  after  us,  I,  seeing  these  many 
evils,  and  the  whole  world  lying,  as  it  were  in  the  wicked  one,  among  the  dead, 
awaiting  death  —  as  I  have  truly  heard  and  examined,  so  have  I  reduced  these 
things  to  writing;  and  lest  the  writing  should  perish  with  the  writer,  and  the 
work  fail  altogether  with  the  workman,  I  leave  parchment  for  continuing  the 


116  THE    PLAGUE 

work,  if  haply  any  man  survive,  and  any  of  the  race  of  Adam  escape  this  pesti- 
lence and  continue  the  work  I  have  commenced. 

It  is  estimated  that  during  the  dark  ages  the  average  of  human 
life  was  less  than  twenty  years.  A  high  birth-rate  was  necessary  to 
keep  the  race  alive,  but  notwithstanding  this,  Europe  was  sparsely 
inhabited.  At  the  time  of  the  Norman  conquest  the  inhabitants  of 
England  numbered  between  two  and  two  and  one-half  million,  prob- 
ably nearer  the  former,  for  they  had  not  reached  the  greater  number 
a  hundred  years  later.  Creighton  says :  "It  would  be  within  the  mark 
to  say  that  less  than  one-tenth  of  the  population  was  urban  in  any 
distinctive  sense  of  the  term.  After  London,  Norwich,  York  and 
Lincoln,  there  were  probably  no  towns  with  five  thousand  inhabitants." 
Indeed,  urban  life,  as  we  now  know  it,  was  quite  impossible  in  this 
age  of  pestilence  and  would  soon  become  so  again  were  the  functions 
of  preventive  medicine  relaxed. 

Most  of  the  great  epidemics  of  the  middle  ages  were  designated 
as  pestilentia  or  magna  mortalitas.  In  the  most  deadly  visitations  the 
bubonic  plague  is  so  accurately  described  that  there  can  be  no  doubt 
about  its  identity,  but  it  must  not  be  supposed  that  the  people  enjoyed 
any  high  degree  of  health  even  in  those  periods  when  this  contagion 
languished  on  account  of  exhaustion  of  susceptible  victims.  Ergotism, 
under  the  name  of  Saint  Anthony's  fire,  was  endemic  in  France  and 
adjacent  territories;  Normandy  was  filled  with  lepers,  but  Christ's 
poor  were  not  confined  to  that  country.  England  was  regarded  as  the 
special  home  of  hunger,  but  abundance  was  a  stranger  to  the  masses 
in  every  land.  The  mysterious  sweating  sickness,  apparently  brought 
to  England  with  Henry  Tudor  in  1485,  developed  in  five  distinct  epi- 
demics which  were  characterized  by  the  fact  that  the  mortality  was 
greater  among  the  rich  than  the  poor.  Typhus,  known  as  morbus 
pauperum,  prevailed  largely  in  the  jails,  on  ships  and  among  the 
squalid  inhabitants  of  the  cities.  Even  the  discovery  of  America  car- 
ried to  Europe  the  scourge  of  syphilis,  which  was  spread  over  Italy 
by  the  soldiers  of  Charles  VIII,  and  within  a  few  years  reached  the 
most  distant  parts  of  Europe.  Smallpox  appeared  in  England  in  the 
sixteenth  century,  having  journeyed,  according  to  the  most  reliable 
authority,  all  the  way  from  the  Orient.  That  tuberculosis,  diphtheria, 
dysentery  and  other  diseases,  still  with  us,  prevailed  during  the  middle 


THE    PLAGUE  117 

ages  is  shown  by  the  records,  but  they  were  overshadowed  by  the 
higher  mortality  of  those  mentioned  above.  Improved  agriculture  has 
extinguished  the  fire  of  St.  Anthony,  except  in  the  most  benighted 
provinces  of  Russia.  The  great  fire  in  London  in  1666  destroyed  the 
infected  rats  and  relieved  England  of  the  bubonic  plague,  which  had 
been  endemic  in  that  country  since  1349.  Something  more  than  one 
hundred  years  later  the  discovery  of  Jenner  robbed  smallpox  of  its 
horrors,  wherever  vaccination  is  properly  enforced.  The  investiga- 
tions of  Howard  improved  the  sanitation  of  jails  and  workhouses,  and 
did  much  to  eradicate  typhus. 

Bacillus. — This  was  discovered  and  isolated  by  Yersin  and  Kitasato 
independently  in  the  epidemic  in  Cochin  China,  and  at  Hongkong 
(1893-94).  Since  the  descriptions  given  by  these  investigators  did 
not  agree  in  every  detail,  it  was  suggested  that  the  organisms  obtained 
by  them  are  not  identical,  but  subsequent  studies  have  shown  that 
they  are  only  slightly  different  strains  of  the  same  bacterium.  The 
bacillus  is  a  short,  plump  rod  with  rounded  ends  and  stains  more 
deeply  at  the  ends  than  in  the  middle — bipolar  staining.  In  length  it 
varies  from  1.5  to  1.7  of  a  micron  and  its  breadth  is  about  one-third 
its  length.  However,  it  manifests  marked  morphologic  variability, 
coccus-like  forms  and  long  rods  being  found  in  the  same  body,  also 
in  the  discharge  from  buboes  and  in  the  sputum.  The  polymorphic 
growth  of  this  bacillus  must  be  held  in  mind  in  making  a  microscopic 
diagnosis,  which  is  easily  done  by  an  expert.  It  takes  the  basic  stains, 
such  as  methylene  blue,  quickly  and  deeply.  Gaffky  recommends  that 
the  dried  smear  be  washed  with  0.5  per  cent,  of  acetic  acid  before  the 
stain  is  applied.  It  is  non-motile,  non-liquefying  and  may  show  a 
mucous  capsule.  However,  this  is  often  not  recognizable,  unless  it 
be  brought  out  by  special  methods.  In  the  first  description  of  his  find, 
Kitasato  made  it  a  motile  organism,  but  subsequently  it  was  shown 
that  such  motility  as  it  may  manifest  is  wholly  passive.  It  is  sporeless, 
but  may  remain  viable  in  culture  for  four  years.  Most  pathogenic 
bacteria  have  their  optimum  growth  temperature  at,  or  slightly  above, 
that  of  the  animal  body.  This  is  not  true  of  the  plague  bacillus.  It 
grows  at  the  temperature  of  man's  body;  otherwise  it  could  not  be 
pathogenic  to  man ;  but  in  artificial  cultures  it  grows  much  more  rap- 


118  THE    PLAGUE 

idly  and  abundantly  some  degrees  lower.  It  grows,  but  Mess  rapidly 
still,  at  febrile  temperatures.  It  develops  on  neutral  and  feebly  alka- 
line media  and  is  an  aerobe.  On  gelatin  plates  at  22  C.  (71.6  F.) 
it  develops  within  three  days  fairly  characteristic  colonies.  The  super- 
ficial ones  project  above  the  surface,  are  coarsely  granular  and  par- 
tially transparent.  They  do  not  liquefy  the  gelatin  and  the  deep 
colonies  are  in  no  way  characteristic.  In  gelatin  stick  cultures,  this 
bacillus  grows  slowly,  but  uniformly  along  the  line.  In  undisturbed 
bouillon,  a  deposit  forms;  later  the  surface  is  covered,  and  stalactites 
and  stalagmites  may  develop.  However,  these  formations,  although 
striking,  are  not  confined  to  cultures  of  the  plague  bacillus.  Hankin 
uses  for  diagnostic  purposes  an  agar  containing  from  2.5  to  3.5  per 
cent,  of  salt.  On  this  medium  well-marked  involution  forms  develop. 
Swollen,  spindle-shaped,  and  ovoid  forms  appear  instead  of  the  normal 
rods.  Other  investigators  claim  that  other  bacteria  grown  on  this 
medium  develop  similar  forms  and  that  this  test  should  not  be  relied 
on  for  diagnostic  purposes.  However,  this  is  largely  a  matter  of 
expert  training.  Hankin  in  the  midst  of  the  plague  in  India  has  in 
all  probability  acquired  an  expertness  which  a  European  laboratory 
worker  with  only  old  cultures  at  hand  is  not  likely  to  secure  after  a 
short  series  of  tests.  The  plague  bacillus  grows  abundantly  on  coagu- 
lated serum,  but  offers  nothing  distinctive  in  such  growths.  It  multi- 
plies slowly  in  sterilized  milk  without  coagulation,  although  there  is 
a  slight  development  of  acid.  In  peptone  solution  and  on  potato  its 
growth  is  slow  and  non-distinctive. 

The  bacillus  may  retain  both  vitality  and  virulence  for  a  long  time 
in  men  and  rats  recovered  from  the  disease.  The  organism  carried  by 
these  hosts,  however,  is  not  always  virulent.  Moreover,  as  a  rule,  men 
and  animals,  recovered  from  the  disease,  are  free  from  the  bacillus. 
Strong  found  that  avirulent  bacilli  injected  subcutaneously  in  apes 
are  wholly  destroyed  within  twenty-four  hours.  As  has  been  said, 
cultures  protected  from  drying  and  from  the  light  may  remain  viable 
after  four  years  and,  indeed,  they  have  been  reported  as  still  virulent. 
Old  subcultures  after  many  years  become  quite  inert.  While  complete 
desiccation  soon  destroys  the  bacillus,  so  long  as  moisture  persists,  its 
destruction  within  a  reasonable  time  is  improbable.  From  this  we 
may  deduce  two  practical  lessons.  The  first  is  that  plague  pus  or 


THE    PLAGUE  119 

sputum  deposited  on  clothing  may  retain  its  vitality  for  months.  The 
second  is  that  air-borne  infection  does  not  play  an  important  role  in 
the  distribution  of  this  disease.  The  last  statement  must  not  be  taken 
as  denying  the  possibility  or  even  the  probability  of  droplet  infection, 
especially  in  pneumonic  cases.  Direct  sunlight  kills  speedily,  the 
time  varying  with  the  thickness  of  the  layer.  Speaking  generally, 
hours  are  necessary.  An  agar  culture  exposed  to  direct  sunlight  con- 
tains virulent  bacilli  after  two  hours  and  bubonic  pus  placed  on  glass 
and  exposed  directly  to  sunlight  is  non-virulent  after  about  six  hours. 
Bouillon  cultures  used  for  immunizing  purposes  are  sterilized  by  heat- 
ing for  one  hour  at  58  C.  (136.4  F.).  Boiling  kills  in  one  minute. 
Dry  heat  at  100  C.  continued  for  one  hour  kills  the  bacillus.  Ordinary 
methods  of  disinfection  suffice  to  destroy  this  organism. 

The  virulence  of  this  bacillus  is  quite  variable.  It  is  probably  true 
that  the  bacterium  from  any  animal  dead  of  this  disease  is  pathogenic 
to  the  rat  and  guinea-pig,  but  some  strains  retain  their  virulence 
through  many  generations  when  grown  artificially,  while  others  soon 
lose  it.  The  virulence  is  more  quickly  lost  at  incubator  than  at  lower 
temperature.  In  order  to  preserve  the  virulence  of  cultures,  passage 
through  susceptible  animals  should  be  resorted  to  from  time  to  time. 
Repeated  animal  passage  may  revive  a  failing  virulence. 

All  rodents  are  susceptible  to  the  plague  bacillus,  but  between  the 
different  species  of  these  there  are  wide  variations.  The  most  sus- 
ceptible is  the  rat,  which  suffers  extensively  from  epidemics  of  this 
disease  and  responds  to  every  form  of  artificial  inoculation.  When  the 
plague  virus  is  rubbed  into  the  shaved  or  clipped  abdomen  of  this 
animal  the  bacillus  finds  its  way  through  the  skin,  apparently  when 
there  is  no  injury,  and  causes  a  general  infection.  When  the  skin  is 
pricked  with  the  finest  infected  needle,  the  nearest  glands  become 
swollen  and  the  neighboring  tissue  edematous,  while  the  infection 
extends  to  other  glands  and  soon  a  general  infection  is  established. 
The  spleen  is  enlarged,  the  lungs  and  liver  become  hyperemic  and 
after  death  the  bacillus  is  found  in  every  part  of  the  body.  When  the 
injection  is  made  into  the  peritoneal  cavity,  the  bacillus  passes  through 
the  peritoneal  walls,  which  seem  only  somewhat  more  moist  than  nor- 
mal, and  reaches  the  various  organs.  Given  by  mouth,  the  first  visible 


120  THE    PLAGUE 

effect  may  be  an  enlargement  of  the  cervical  glands,  or  the  mucous 
membrane  of  the  stomach  and  small  intestine  may  become  inflamed  and 
hemorrhagic  and  the  mesenteric  and  other  glands  may  be  enlarged. 
Either  form  of  the  disease  may  develop  and  in  any  case  the  disease 
terminates  fatally.  When  a  dilute  culture  is  painted  on  the  mucous 
membrane  of  the  nose  carefully  to  avoid  abrasion  or  dropped  into  the 
conjunctival  sac,  general  infection,  the  pneumonic  or  the  bubonic  form, 
develops. 

McCoy  found  that  the  ground  squirrel  and  the  rock  squirrel  of 
California  are  quite  as  susceptible  as  the  rat.  Strong  and  others  in  the 
study  of  the  Manchurian  outbreak  place  the  Siberian  marmot  in  the 
same  list.  All  these  animals  develop  epidemics  of  the  plague. 

The  guinea-pig  is  slightly  less  susceptible  than  the  above  named 
animals  to  the  plague  bacillus  on  inoculation.  No  outbreak  of  the 
plague  in  the  guinea-pig  in  its  native  state  is  recorded,  but  there  was 
an  epidemic  among  these  animals  in  the  Zoological  Garden  at  Sydney 
in  1902.  Both  gray  and  white  mice  are  susceptible  and  may  acquire 
the  disease  by  feeding  on  infected  material.  Rabbits  are  somewhat 
less  susceptible  than  guinea-pigs  and  mice.  They  are  killed  by  sub- 
cutaneous inoculations,  but  are  not  affected  by  feeding.  Cats  may 
acquire  the  disease  through  eating  infected  mice  or  rats.  Hunter 
reports  such  cases  from  Hongkong.  Ferrets,  also  used  in  destroying 
rats,  may  succumb  when  the  feeding  is  long  continued.  Hyenas, 
jackals  and  dogs  are  only  slightly  susceptible,  especially  by  way  of  the 
mouth.  According  to  Toyama,  the  Japanese  bat  is  quite  susceptible. 
Wilson  reports  an  epidemic  among  hogs  in  Hongkong.  Cattle,  sheep, 
goats  and  horses  are  not  susceptible.  Subcutaneous  inoculations  in 
these  animals  are  followed  by  local  reactions,  but  general  infection 
does  not  result.  The  testimony  concerning  the  susceptibility  of  birds, 
reptiles,  amphibians  and  fish  is  conflicting,  but  it  seems  to  be  safe  to 
say  that  these  animals  play  no  part  in  the  distribution  of  the  disease. 

In  his  early  work,  Yersin  observed  that  an  unusual  number  of  the 
flies  in  his  workroom  died  and  later  Nuttall  showed  that  the  fly  may 
be  infected,  fatally  to  itself  and  may  distribute  the  disease.  The 
plague  bacillus  has  been  found  in  ticks,  ants  and  lice.  The  role  played 
by  the  flea  in  this  disease  will  be  discussed  later. 


THE    PLAGUE  121 

Apes  resemble  man  in  their  susceptibility  to  plague,  developing 
both  the  pneumonic  and  bubonic  forms.  Epidemics  among  these  ani- 
mals have  been  reported. 

Modes  of  Infection. — According  to  Dieudonne  and  Otto  there  are 
five  geographical  foci  where  the  plague  is  endemic  and  from  which 
it  is  spread  to  diverse  parts  of  the  earth.  Four  of  these  are  in  Asia 
and  one  in  Africa.  The  first  lies  in  the  Kwen-Fun  mountains  in  the 
Eastern  Himalayas.  From  this  place  the  plague  extended  in  1893  to 
Cochin  China  and  Hongkong.  The  second  is  in  the  southwestern  foot- 
hills of  the  Himalayas.  From  this  place  the  disease  spread  over 
India,  reaching  Bombay  in  1896  and  at  the  same  time  it  traversed 
Persia  and  reached  the  Black  sea,  invading  Russia  by  way  of  Samar- 
kand. This  focus  has  a  population  of  about  one  million,  and  English 
physicians  have  reported  thirty  smaller  or  larger  epidemics  in  this 
region  between  1823  and  1897.  Many  of  these  resembled  the  black 
death  of  the  middle  ages  and  were  certainly  the  pneumonic  form  of 
the  plague.  These  epidemics  affected  both  men  and  rats.  Among  the 
latter  there  exists  a  chronic  plague  which  serves  to  keep  the  bacillus 
alive  and  virulent. 

The  third  region  is  the  most  extensive,  covering  northern  Mongolia 
and  the  Kirghiz  Steppes.  From  this  locality  the  plague  in  highly 
virulent  form  spread  over  Manchuria  in  the  winter  of  1910-11.  The 
infection  of  this  region  was  first  investigated  in  1895  by  two  Russian 
physicians  who  discovered  what  has  since  been  known  as  the  "tara- 
bagan"  plague.  The  tarabagan  or  Siberian  marmot  is  a  small  animal, 
widely  distributed  in  the  mountains  about  Lake  Baikal  and  over  the 
high  table-land  of  Western  Siberia.  It  lives  in  large  families  in 
excavations  which  they  make  and  which  are  several  feet  deep.  They 
leave  their  homes  in  great  numbers  in  the  fall  in  search  of  food.  They 
are  valuable  on  account  of  their  fur  and  many  of  them,  being  ill  with 
the  plague,  are  easily  captured.  It  has  long  been  known  that  men 
become  infected  with  a  highly  fatal  disease  in  skinning  the  animals. 
The  bacillus,  having  found  a  human  host,  is  spread  from  man  to  man. 
The  crowded  life  in  small  huts  during  the  winter  favors  the  spread  of 
the  infection.  Whole  communities  are  wiped  out  and  in  fear  many 
flee  to  adjacent  territory,  carrying  the  disease  with  them.  The  mar- 


122  THE    PLAGUE 

mots  die  in  great  numbers  and  are  eaten  by  dogs  and  wolves.  It  is 
not  known  whether  these  animals  are  infected  from  such  food  or  not. 
It  is  not  supposed  that  they  play  an  important  role  in  the  transmission 
to  man.  In  man  the  pneumonic  form  of  the  plague  is  most  in  evi- 
dence, and  the  bacillus  is  disseminated  by  droplets  in  talking,  sneez- 
ing and  coughing.  The  cervical  glands  are  often  involved,  the  inguinal 
less  frequently.  The  fourth  Asiatic  focus  lies  in  the  mountains  on  the 
southwest  coast  of  Arabia  in  the  region  of  Assir  on  the  Red  Sea. 
This  region  has  not  been  closely  studied.  The  African  nursery  is 
found  in  Uganda  near  the  source  of  the  White  Nile.  It  is  supposed 
that  this  region  is  the  breeding  place  of  the  pestilence  which  has  given 
Egypt  an  evil  reputation  for  so  many  centuries. 

The  distribution  from  these  centers  and  from  secondary  foci  fol- 
lows lines  of  traffic,  penetrating  distant  lands  and  traversing  the  widest 
seas. 

The  infection  in  man  may  be  transferred  directly  from  one  to  the 
other.  This  is  the  chief  method  of  spread  in  the  pneumonic  form. 
The  sputum  is  full  of  the  bacilli  and  in  crowded  families  droplet  infec- 
tion is  most  common.  Among  the  more  civilized  and  the  better  housed 
peoples,  this  method  of  transmission  is  rapidly  becoming  less  potent. 
In  1900  out  of  276  cases  in  Sydney  there  were  only  ten  houses  in 
which  more  than  one  case  developed.  While  "carriers"  play  an  unim- 
portant role  in  the  transmission  of  the  plague,  it  is  known  that  those 
recovering  from  the  pneumonic  form  may  suffer  from  a  more  or  less 
chronic  bronchitis  in  which  the  sputum  remains  infective.  The 
bubonic  form  does  not  favor  direct  transmission,  but  in  this  form  the 
transfer  may  be  indirect,  by  soiled  clothing  and  infected  houses.  It 
has  long  been  known  that  poverty  and  hunger  favor  the  spread  of 
this  disease.  Undoubtedly  ignorance  and  filthy  habits  are  also  impor- 
tant factors.  The  figures  from  Bombay  show  the  following  distribu- 
tion per  million  among  the  several  classes :  Low  caste  Hindoos,  53.7 ; 
Brahmins,  20.7;  Mohammedans,  13.7;  Eurasians,  6.1;  Jews,  5.2; 
Parsees,  4.6 ;  Europeans  0.8. 

The  rat  has  long  been  suspected  as  playing  a  part  in  the  distribu- 
tion of  this  disease.  In  the  great  epidemics  of  the  middle  ages  it  was 
observed  that  rats  come  from  their  holes,  lose  all  fear  of  man,  become 
uncertain  in  movement  and  die  in  great  numbers.  The  most  ignorant 


THE    PLAGUE  123 

came  to  regard  deaths  among  rats  as  foretelling  the  coming  of  the 
plague  and  fled  from  their  homes,  when  confronted  with  this  evidence. 
The  discovery  of  the  bacillus  and  the  study  of  its  effects  on  the  lower 
animals,  as  well  as  on  man,  has  at  least  partially  cleared  up  the 
mystery,  although  there  are  still  unsolved  problems.  Rodents  are  the 
most  active  distributors  of  this  disease.  They  carry  the  infection  from 
house  to  house,  from  village  to  village,  and  from  home  ports  to  distant 
lands.  The  first  appearance  of  the  disease  in  a  country  previously 
free  from  the  infection  occurs  in  those  occupied  about  the  docks, 
receiving  grain  and  other  commodities  from  infected  lands.  Generally 
before  a  case  has  occurred  in  man  the  wharf  rats  are  observed  to 
behave  peculiarly  and  then  to  die  in  large  numbers.  An  infected  rat 
has  landed  from  the  ship  and  has  infected  others.  How  does  one  rat 
infect  others  ?  The  most  probable  answer  to  this  question  is  that  the 
sick  new  arrivals,  one  or  more,  have  died  and  the  natives  have  fed 
on  the  corpse  and  acquired  the  infection  in  this  way.  While  a  hungry 
rat  may  feed  on  the  dead  of  its  own  species,  it  seems  to  prefer  other 
food.  Moreover,  in  a  dead  rat  the  bacilli  of  plague  do  not  retain  their 
virulence  for  many  days,  the  exact  time  varying  with  the  temperature. 
While  a  rat  may  be  infected  by  feeding  on  a  dead  fellow,  it  is  much 
more  susceptible  to  inoculation  through  the  skin.  The  conclusion  is 
that  while  this  method  of  transfer  may  and  probably  does  occur,  it  is 
not  the  sole  or  even  the  most  important  method,  and  we  shall  look 
farther. 

The  urine  and  feces  of  the  infected  rat  may  be  deposited  on  grain 
or  other  kinds  of  food  and  eaten  by  the  native  animal.  This  is  a 
possibility  easily  submitted  to  experiment.  It  has  been  tried  and  has 
failed  in  all  cases.  Corn  and  other  grains  have  been  mixed  with  the 
urine  and  feces  of  infected  rats  and  fed  to  sound  ones  with  wholly 
negative  results. 

Rats  serve  as  hosts  to  several  parasites,  among  which  is  the  rat 
flea  (Pulex  cheopis)  and  possibly  this  may  serve  in  the  transfer  of  the 
bacillus  from  one  rat  to  another.  In  the  first  place  this  flea  is  taken 
from  an  infected  rat,  examined  and  found  to  contain  the  bacillus  of 
plague.  This  seems  to  be  a  step  in  the  right  direction.  Such  a  flea 
is  crushed,  a  needle  touched  with  the  material  is  used  to  prick  a 
healthy  rat  and  this  animal  becomes  infected  and  dies  of  the  plague. 


124  THE    PLAGUE 

Infected  rats  are  kept  in  one  side  of  a  cage,  uninfected  ones  in  the 
other  side.  So  long  as  the  two  are  separated  by  a  flea-proof  partition 
the  infection  is  not  transmitted.  Even  when  the  partition  is  made  of 
tangle-foot  which  catches  the  flea  when  it  tries  to  pass  to  the  other 
side,  the  sound  rat  remains  sound.  When  such  a  partition  is  removed, 
the  sound  rat  becomes  infected.  Rat  fleas  are  captured  and  fed  on 
cultures  of  the  plague  bacillus  and  then  freed  in  a  cage  occupied  by 
healthy  rats  which  soon  become  infected.  Infected  rats  are  stripped 
of  all  their  fleas  and  then  placed  in  cages  with  healthy  ones,  which 
remain  uninfected.  Infected  rats  carrying  their  fleas  are  caged  with 
guinea-pigs,  and  the  latter  become  infected. 

These  with  many  other  variations  on  the  experiment  have  been 
made,  and  show  conclusively  that  the  plague  is  transferred  from  rat 
to  rat  or  from  rat  to  guinea-pig  by  the  bite  of  the  rat  flea.  This 
question  is  satisfactorily  answered. 

How  is  the  plague  transferred  from  rat  to  man?  Evidently 
experiment  along  this  line  might  be  open  to  serious  criticism  and  we 
must  depend  on  observation,  which  is  never  so  thoroughly  convincing 
as  experiment.  Will  the  rat  flea  bite  man  and  if  it  does  will  such  a 
flea  bearing  the  plague  bacillus  infect  man?  While  we  cannot  use 
man  in  this  experiment,  we  may  employ  his  nearest  relative,  the  ape. 
The  rat  flea  does  bite  the  ape,  and  if  the  flea  is  infected  with  the 
plague  bacillus  its  bite  induces  this  disease  in  the  ape.  It  is  the  testi- 
mony of  several  observers  that  uninfected  rat  fleas,  while  preferring 
their  own  host,  will  in  its  absence  feed  on  man. 

Liston  reports  that  in  a  certain  house  in  India  on  April  6,  1904, 
many  rats  were  found  dead;  on  April  11  the  house  was  so  infested 
with  fleas  that  the  occupants  sought  sleep  on  the  veranda.  On  April 
17,  two  of  these  people  were  stricken  with  the  plague.  On  April  20, 
thirty  fleas  were  captured  in  this  house  and  of  these  fourteen  were 
rat  fleas,  while  of  246  fleas  captured  in  uninfected  houses,  not  one  was 
a  rat  flea.  Tidswell  of  Sydney  states  that  on  a  wharf  where  many 
rats  were  dead  he  was  violently  attacked  by  fleas. 

It  has  happened  that  in  some  localities  rats  die  of  the  plague,  while 
there  is  no  infection  among  men.  This  is  explained  by  the  absence 
of  the  flea,  which,  while  widely  distributed,  is  not  found  on  all  rats 
at  all  times.  However,  there  is  another  factor  which  needs  considera- 


THE    PLAGUE  125 

tion.  In  the  transmission  of  the  plague  from  rats  to  man  by  the  flea 
there  is  a  time  of  variable  length  during  which  the  flea  is  on  neither 
rat  nor  man.  The  duration  and  conditions  of  this  interval  are  widely 
variable  and  not  equally  favorable  to  the  transmission  of  the  disease. 
In  a  hot,  dry  climate  rat  fleas  soon  die  when  detached  from  their  hosts. 
Local  conditions  may  play  an  important  role  in  the  transfer  of  the 
infected  flea  from  rat  to  man. 

I  think  that  it  must  be  admitted  that  the  evidence  in  favor  of  the 
possibility  of  the  transfer  of  the  plague  from  rat  to  man  through  the 
flea  is  strongly  positive.  Whether  this  is  accomplished  through  other 
agencies  or  not  is  an  open  question. 


CHAPTER    XIII 


SYMPTOMATIC    ANTHRAX 

History. — Under  various  names,  such  as  "blackleg,"  "quarter  evil" 
in  English ;  "Charbon  Symptomatique"  in  French ;  and  "rauschbrand" 
in  German,  this  disease  has  been  a  cattle  scourge  for  centuries.  We 
owe  our  first  and  most  valuable  knowledge  concerning  it  to  French 
investigators.  As  early  as  the  eighteenth  century  it  was  shown  by  the 
studies  of  Chabert  and  Boutrolle  to  be  a  specific  disease.  The  most 
thorough  studies  of  the  nineteenth  century  were  made  by  Arloing, 
Cornevin  and  Thomas  of  Lyons.  As  early  as  1879  these  men  recog- 
nized the  infectious  nature  of  the  disease  and  began  their  work  on  the 
bacillus,  the  pathology  and  the  immunology  of  this  pest.  It  is  con- 
fined to  cattle  and  no  case  of  infection  in  man  has  been  observed. 

The  Bacillus.  —  This  organism  is  generally  known  as  Bacillus 
chauvei,  from  the  distinguished  French  veterinarian  Chaveau.  It  is 
a  large,  spore-forming  anaerobic  bacillus,  sometimes  growing  in  chains, 
but  usually  in  separate  rods.  The  diameter  of  the  spores  being  much 
greater  than  the  breadth  of  the  rod  and  the  location  being  at  or  near 
the  middle,  the  spore-bearing  rod  has  a  peculiar  appearance  well 
designated  as  "snowshoe"  or  "whetstone."  In  old  cultures  free  spores 
may  be  seen  and  sometimes  are  numerous.  The  spores  are  highly 
resistant  to  heat  and  chemical  disinfectants,  and  when  a  locality 
becomes  infected  eradication  of  the  disease  is  not  easy.  This  organism  is 
is  not  nearly  so  virulent  as  the  anthrax  bacillus,  one  rod  of  which  suffices 
to  infect  a  guinea-pig  fatally,  while  many  hundred  rods  of  the  symptom- 
atic anthrax  bacillus  may  fail  to  induce  a  like  result.  Infection  fol- 
lows subcutaneous  and  intramuscular  injections.  In  guinea-pigs  the 
period  of  incubation  after  artificial  inoculation  runs  from  twelve  to 
twenty-four  hours,  depending  on  the  amount  and  virulence  of  the  cul- 
ture employed.  The  animal  ceases  to  feed  and  soon  begins  to  develop 
an  edematous  area  about  the  point  of  inoculation.  However,  if  this 
be  directly  on  the  back,  the  edema  is  more  marked  on  the  sides  than 


128  SYMPTOMATIC    ANTHRAX 

directly  about  the  site  of  injection.  At  first  the  edematous  areas  are 
soft  and  pasty ;  later  gas  accumulates  and  they  become  crepitant.  This 
continues  for  from  twenty-four  to  forty-eight  hours,  when  the  ani- 
mal shows  agonal  breathing  and  dies  either  in  convulsions  or  coma. 
In  certain  instances  the  development  of  the  infection  is  atypical.  It 
proceeds  less  rapidly,  leads  to  the  formation  of  an  abscess  and  ulti- 
mately ends  in  recovery.  On  necropsy  the  subcutaneous  tissue  is  found 
impregnated  with  bloody  fluid  and  distended  with  gas.  In  the  serous 
cavities,  pleura,  peritoneum  and  pericardium,  there  are  exudates,  more 
or  less  stained  with  blood  and  often  coagulated.  The  heart  is  soft  and 
distended ;  the  liver  and  kidneys  hyperemic ;  the  lungs  anemic ;  and  the 
spleen  normal  in  size.  This  is  practically  the  symptomatology  of  the 
disease  in  cattle.  Young  animals  are  most  susceptible  and  die  within 
a  few  hours  after  the  first  indication  of  being  ill.  The  disease  is  widely 
distributed  and  has  been  the  cause  of  great  commercial  loss.  It  is  most 
prevalent  during  the  summer  and  early  fall  and  in  low-lying  meadows 
and  along  water  courses.  Just  how  animals  become  infected  is  not 
known,  but  it  is  generally  supposed  that  the  virus  finds  entrance 
through  some  accidental  wound.  To  one  who  has  seen  herds  of  calves 
die  within  a  few  days  from  this  disease,  this  explanation  is  not  wholly 
satisfying.  It  is  not  probable  that  all  the  animals  in  the  herd,  or  even 
a  large  percentage  of  them,  carried  accidental  wounds  at  the  same 
time.  No  insect  has  been  convicted  of  this  crime  up  to  the  present 
time.  The  infection  is  not  transmitted  by  feeding  and,  strange  to  say, 
animals  bear  without  infection  large  intravenous  injections  of  pure 
cultures,  provided  that  none  of  the  fluid  finds  its  way  into  the  sub- 
cutaneous tissues. 

While  epidemics  have  been  observed  only  in  cattle,  possibly  a  few 
in  hogs,  many  animals  are  susceptible  to  direct  inoculation  into  the 
subcutaneous  or  muscular  tissue.  Rabbits,  white  rats,  and  mice  are 
refractory,  but  may  succumb  to  large  inoculations. 

The  bacillus  grows  best  on  a  medium  containing  an  emulsion  of 
brain  tissue.  As  has  been  stated,  it  does  not  grow  in  the  presence  of 
oxygen  and  deep  intramuscular  injections  are  more  certainly  fatal 
than  subcutaneous  ones.  Injections  into  serous  cavities  are  generally 
without  effect.  Bacilli  introduced  into  these  cavities  are  speedily 
devoured  by  the  phagocytes.  When  injected  with  lactic  acid,  which 


SYMPTOMATIC    ANTHRAX  129 

repels  the  phagocytes,  the  bacilli  develop.  Inoculations  on  the  ears  or 
the  tail  induce  only  local  reactions  and  cause  a  degree  of  immunity. 
The  farther  from  the  root  of  the  tail  the  less  marked  is  the  effect. 
When  an  inoculation  into  the  tail  has  been  made  and  the  site  kept 
covered  with  an  ice  bag,  the  area  of  involvement  is  restricted  and  may 
escape  detection.  On  the  other  hand,  if  the  site  of  inoculation  on 
the  tail  be  kept  covered  with  warm  poultices  the  area  involved  is  more 
extensive  and  a  general  infection  may  result. 

Much  has  been  done  in  the  immunization  of  animals  to  this  dis- 
ease, although  an  ideal  process  has  not  been  developed.  The  funda- 
mental facts  have  been  supplied  by  French  investigators.  At  first  they 
employed  intravenous  injections  of  fully  virulent,  even  spore-bearing 
cultures.  Cattle  bear  up  to  6  c.c.  of  such  cultures  administered  in 
this  way.  A  slight  febrile  reaction  follows  and  after  this  the  animal 
is  immune.  As  a  laboratory  method  and  in  skilled  hands  this  method 
works,  but  it  fails  in  unskilled  hands  in  the  field,  because  some  of  the 
fluid  is  injected,  not  directly  into  the  blood  current  but  into  the  tis- 
sues, and  fatal  infection  follows.  The  second  method  consisted  in  the 
subcutaneous  inoculation  of  virulent  cultures  in  the  tail.  In  this  local- 
ity the  organism  develops  slowly  and  the  phagocytes  finally  destroy 
them.  A  small  pledget  of  cotton  which  has  been  moistened  in  a  culture 
is  introduced  under  the  skin  on  the  tail.  This  method  has  been  used 
widely  and  successfully  in  Alsace-Lorraine  and  in  Holland.  A  third 
method  consists  in  the  employment  of  two  vaccines.  The  first  is  a 
culture  heated  for  six  hours  at  100  to  104  C. ;  the  second  is  heated 
for  the  same  time  at  90  to  95  C.  These  are  dried,  ground  and  dis- 
tributed in  packages  bearing  directions.  The  first  vaccine  is  intro- 
duced under  the  skin  of  the  tail  three  hand's  breadths  from  the  root 
and  the  second,  ten  to  fourteen  days  later  one  hand's  breadth  from 
the  root  of  the  tail.  On  account  of  the  time  required  to  make  two 
inoculations  this  method  has  been  cut  down  to  the  use  of  one  vac- 
cine heated  to  from  95  to  100  C.  and  the  inoculation  is  made  on  the 
shoulder. 

The  method  of  Norgaard  is  followed  by  the  Bureau  of  Animal 
Industry  in  this  country.  The  tissue  of  a  fresh  tumor  is  pulverized, 
extracted  with  water  and  strained  through  cloth.  The  filtrate  is  dried 
to  a  brown  scale,  which  is  sent  out  in  packages  with  directions  for 


130  SYMPTOMATIC    ANTHRAX 

using.  The  powder  is  dissolved  in  water,  heated  for  six  hours  at 
from  95  to  100  C,  and  injected  into  the  animal.  The  number  of 
doses  of  this  vaccine  used  annually  in  this  country  amounts  to  more 
than  a  million  and  a  quarter.  This  has  greatly  decreased  the  loss  from 
this  disease. 

In  1911  Foth  announced  the  preparation  of  a  superior  vaccine  for 
symptomatic  anthrax.  Massive  cultures  are  filtered  through  a  hard 
paper  and  the  filtrate  precipitated  with  alcohol.  This  precipitate  pro- 
tects both  cattle  and  guinea-pigs,  and  its  strength  can  be  more  accur- 
ately determined  than  the  older  vaccines.  However,  its  practical  use 
on  a  large  scale  has  not  yet  been  demonstrated. 


CHAPTER    XIV 


MALIGNANT    EDEMA 

History. — This  is  a  rare  disease  and  it  is  impossible  to  secure  any 
exact  information  concerning  its  prevalence  in  past  ages.  In  1877 
Pasteur  introduced  bits  of  putrid  flesh  under  the  skin  of  guinea-pigs 
and  rabbits,  and  thus  induced  a  rapidly  progressive  disease  character- 
ized by  the  accumulation  of  fluid  in  the  subcutaneous  tissue.  He  was 
able  to  transfer  the  disease  from  one  animal  to  another  and  found 
that  it  was  due  to  a  rod-shaped,  spore-bearing  organism  which  he 
designated  as  Vibrion  septique.  In  1881  Koch  continued  this  work 
and  since  that  time  the  disease  has  been  known  as  malignant  edema. 

The  Bacillus. — It  is  still  a  question  whether  there  is  only  one  or 
several  closely  related  organisms  capable  of  inducing  this  pathologic 
condition.  Even  when  the  same  strain  is  employed  in  experimental 
inoculation,  the  effects  are  not  always  exactly  the  same.  The  fluid 
which  collects  in  the  subcutaneous  tissue  may  be  only  slightly,  or 
markedly,  bloody  and  the  infiltration  may  be  accompanied  by  the 
evolution  of  more  or  less  gas.  The  typical  bacillus  is  a  rod  with 
rounded  ends,  slightly  motile,  growing  in  the  absence  of  air,  and 
developing  spores.  It  liquefies  gelatin  and  blood  serum,  coagulates 
milk  and  then  digests  the  coagulum.  It  produces  abundant  gas  in 
media  containing  glucose  and  traces  of  gas  in  media  practically 
free  from  carbohydrates.  Horses,  cattle,  hogs,  and  sheep  are  sus- 
ceptible, but  infection  probably  never  occurs  except  through  a  wound 
either  on  the  skin  or  the  mucous  membrane.  It  is  one  of  the  sequelae 
of  castration  in  males  and  of  birth  in  females  among  our  domestic 
animals,  although  even  in  these  conditions  it  is  quite  rare.  When 
infected  matter  is  taken  into  the  alimentary  canal  it  passes  through 
without  doing  harm  unless  there  be  some  break  in  the  mucous  mem- 
brane. When  it  infects  man  and  the  larger  animals,  the  bacillus  is 
found  abundantly  in  the  edematous  fluid,  but  seldom  widely  dis- 
tributed through  the  body.  This  indicates  that  it  kills  by  the  elabora- 


132  MALIGNANT    EDEMA— GAS    PHLEGMON 

tion  of  a  soluble  toxin.  In  smaller  animals,  such  as  mice  and  guinea- 
pigs,  a  general,  systemic  infection  may  develop.  In  some  instances 
the  diseased  condition  becomes  evident  within  a  few  hours  after  inocu- 
lation. The  tissue  around  the  point  of  introduction  becomes  edema- 
tous  and  the  involved  area  rapidly  extends  and  death  may  follow 
within  twenty-four  hours.  Outside  of  putrid  flesh,  the  bacillus  has 
been  found  in  polluted  soil,  in  which  the  spores  may  retain  both  vital- 
ity and  virulence  for  a  long  time.  The  spores  generally  develop  in  the 
middle  of  the  rod,  making  it  spindle-shaped. 

GAS    PHLEGMON 

There  are  many  related  bacteria  which  when  introduced  through 
wounds  cause  death  of  tissue  with  the  evolution  of  gas.  The  best 
known  of  these  organisms  are  the  following: 

1.  The  Welch  bacillus,  discovered  in  1891  and  known  as  Bacillus 
aerogenes  capsulatus. 

2.  The  Ghon-Sachs  bacillus,  isolated  in  1903  from  a  patient  in  a 
case  of  gaseous  gangrene. 

3.  The  Novy  bacillus,  found  in  milk  in  1894  and  described  under 
the  name  of  Bacillus  edematis  maligni  II. 

4.  Hibier's  bacillus,  found  in  1894  in  a  case  of  gaseous  gangrene, 
developing  after  a  complicated   fracture  in   which  the  wound  was 
polluted  with  earth. 

5.  The  Klein  bacillus,  found  in  the  stool  of  a  person  suffering 
from  acute  enteritis. 

6.  The  Stolz  bacillus,  found  in  a  case  of  gas  phlegmon  following 
a  fracture. 

Besides  the  above  and  other  related  organisms,  the  colon  and 
proteus  may  develop  gas  phlegmon  with  rapidly  progressive  and 
destructive  changes  under  certain  conditions,  as  for  instance,  in  those 
debilitated  by  diabetes.  All  of  these,  with  the  exception  of  the  two 
last  mentioned,  are  spore-bearing,  anaerobic  organisms,  which  are 
found  in  polluted  soil  and  become  infective  only  through  wounds.  The 
mortality  among  the  infected  is  high. 


CHAPTER    XV 


GLANDERS 

History. — As  early  as  the  fourth  century  the  infective  nature  of 
this  disease  was  held  by  a  few  observing  men.  In  the  seventeenth 
century  Solleysel  taught  that  glanders  is  highly  infectious,  may  extend 
from  stall  to  stall,  and  that  the  air  becomes  impregnated  with  the 
infection.  In  the  next  century  certain  French  veterinarians  recom- 
mended that  diseased  horses  should  be  isolated,  observed,  and  if  found 
to  have  glanders  should  be  killed.  In  the  last  decennium  of  the  eight- 
eenth century  a  Danish  veterinarian,  Viborg,  inoculated  sound  horses 
with  pus,  blood,  nasal  secretions,  saliva,  urine  and  perspiration  from 
glandered  animals,  and  succeeded  in  transmitting  the  disease.  He 
showed  that  heat  destroys  the  infective  agent.  Later  it  was  shown 
that  donkeys,  goats,  sheep,  dogs,  cats,  rabbits  and  guinea-pigs  are 
susceptible.  This  work  led  to  experiments  with  the  view  of  disinfecting 
the  discharges  and  stalls  which  had  been  occupied  by  diseased  ani- 
mals. Chaveau  showed  that  the  infection  is  carried,  for  the  most 
part  at  least,  in  the  corpuscular  elements  of  the  discharges.  In  1881 
Babes  and  Havas  of  Roumania  found  bacilli  in  the  pus  from  an  abscess 
on  a  man  who  had  the  disease.  Bouchard  and  others  saw  the  organ- 
ism, but  its  isolation  and  identification  resulted  from  the  work  of 
Loffler  and  Schutz  (1882).  Certain  cases  of  glanders  remained  diffi- 
cult of  diagnosis  because  of  the  organs  involved,  there  being  no  avail- 
able discharge.  The  discovery  of  mallein  by  two  Russian  physicians 
in  1890  and  the  demonstration  that  this  is  a  valuable  diagnostic  agent, 
as  tuberculin  is  in  tuberculosis,  made  the  recognition  of  these  occult 
cases  possible  and  aided  greatly  in  the  restriction  of  the  disease.  Acute 
glanders,  which  is  seen  both  in  men  and  horses,  is  a  rapidly  fatal  dis- 
ease. After  a  short  (from  two  to  five  days)  incubation  period  the 
temperature  often  becomes  very  high  (106-107  F.),  there  is  marked 
prostration  and  great  pain  in  the  joints  and  limbs.  Local  ulceration 
deepens  rapidly  and  boils  and  abscesses  appear  on  various  parts  of 


134  GLANDERS 

the  body  and  rapidly  destroy  skin,  subcutaneous  tissue  and  muscle, 
exposing  blood  vessels,  tendons  and  bones.  Death  usually  occurs  in 
from  one  to  three  weeks.  The  most  frequent  primary  lesion  is  in  the 
nose,  though  it  may  occur  in  the  larynx,  lungs  or  from  a  wound  on 
any  part  of  the  body.  In  about  90  per  cent,  of  the  cases,  the  course 
is  chronic  and  may  continue  for  years.  The  chronic  form  in  man  is 
by  no  means  always  fatal,  the  percentage  of  recovery  given  by 
Bellinger  being  as  high  as  50 ;  but  no  one  else  agrees  with  this  estimate. 

The  Bacillus. — Bacillus  mallei  is  a  slightly  bent  rod  with  rounded 
ends,  whose  length  varies  from  one  to  two-thirds  the  diameter  of  red 
blood  corpuscles.  It  is  sporeless,  non-motile  and  non-liquefying.  It 
takes  the  ordinary  basic  stains,  as  methylene  blue  and  gentian  violet, 
fairly  well,  but  when  intensive  coloring  is  desired  it  is  better  to  select 
a  stain  containing  a  mordant,  such  as  carbol-fuchsin.  The  stain  is 
easily  removed  with  dilute  mineral  acid.  This  bacillus  grows  on  all 
ordinary  culture  media  without  characteristic  appearances  except 
on  potato.  On  the  second  day  a  typical  potato  culture  shows  a  hard, 
yellowish,  transparent  growth.  This  general  appearance,  which  has 
been  likened  to  that  of  a  layer  of  liquid  honey,  continues  until  from 
the  sixth  to  eighth  day,  when  the  transparence  gradually  disappears 
and  the  color  takes  on  a  red  tint  resembling  that  of  cuprous  oxid. 
The  boundaries  of  the  growth  show  a  slightly  greenish  tint,  while  the 
uncovered  surface  of  the  potato  is  grayish  white.  While  the  growth 
on  potato  is  quite  unusual,  it  is  not  sufficiently  characteristic  to  form 
the  sole  basis  in  identification.  For  a  sporeless  organism,  it  may,  when 
protected  from  the  light,  retain  its  vitality  for  an  unusually  long  time. 
Wladmiroff  states  that  the  organisms  from  glycerin-bouillon  tubes, 
with  the  ordinary  cotton  plug,  were  found  viable  after  four  years. 
Direct  sunlight  destroys  this  organism  within  from  a  few  hours  to  a 
few  days  depending  on  the  thickness  of  the  layer  and  the  intensity  of 
the  light.  Bacillus  mallei  is  rather  resistant  to  mercuric  chlorid,  but  is 
easily  destroyed  by  phenol  (2  per  cent.),  zinc  chlorid  (2  per  cent.), 
and  lime  water  (saturated  solution).  The  disinfection  of  stables  with 
gaseous  agents  is,  as  a  rule,  not  feasible  on  account  of  the  openness  of 
barns.  Saturated  lime  water  is  the  best  thing  to  use. 

Avenues  of  Infection. — Many  experiments  have  tested  the  possi- 
bility of  glanders  infection  through  the  unbroken  skin,  and  while  the 


GLANDERS  135 

results  are  negative  so  long  as  the  skin  remains  without  a  break,  a 
minute  lesion,  enough  to  offer  an  atrium  to  a  bacillus,  is  easily  made. 
Babes  and  Cornil  rubbed  an  ointment  containing  the  bacilli  on  the 
shorn  abdomen  of  guinea-pigs  and  succeeded  in  infecting  them,  prob- 
ably through  the  hair  follicles  or  some  lesion  not  recognizable.  It 
seems  also  probable  that  the  unbroken  mucous  membranes  of  the  nasal 
cavities  exclude  the  bacilli,  but  in  neither  man  nor  horse  is  this  struc- 
ture likely  to  remain  without  microscopic  lesions  for  any  great  length 
of  time.  This  is  especially  true  of  the  horse,  on  account  of  the  char- 
acter of  its  food.  Beards  and  husks  and  dust  are  constantly  being 
inhaled  while  the  animal  eats,  and  injury  of  the  mucous  membrane 
of  the  upper  air  passages  is  a  frequent  occurrence.  The  mucous  mem- 
brane of  the  mouth  is  scarcely  less  exposed  to  slight  but  frequent 
insult.  That  the  glanders  bacillus  may  find  its  way  through  the  intes- 
tinal walls,  leaving  no  recognizable  lesion,  and  first  manifest  itself 
in  the  lungs  has  been  demonstrated  by  the  researches  of  Nocard. 
Although  LofHer  reports  a  case  of  human  infection  through  milk,  the 
instance  is  questioned  because  other  sources  of  infection  were  not 
excluded.  Under  Viborg's  efforts  one  hundred  army  horses,  found 
to  be  infected,  were  slaughtered  in  Copenhagen  and  their  flesh  used  as 
food  without  ill  effects.  Similar  instances  on  a  smaller  scale  have 
been  reported  elsewhere.  The  possibility  of  intr^-uterine  infection  in 
case  of  a  diseased  mother  is  recognized  and,  indeed,  such  cases  have 
been  reported  in  both  France  and  Italy.  Of  all  domestic  and  men- 
agerie animals,  cows  and  the  house  rat  are  the  only  ones  that  are 
known  to  be  immune  to  glanders,  although  others  differ  much  in 
degree  of  susceptibility. 


CHAPTER    XVI 


BOTULISM— SAUSAGE    POISONING 

History. — In  certain  parts  of  Germany,  especially  in  Wurtemburg 
and  neighboring  sections  of  Baden  and  Bavaria,  where  sausage,  a 
favorite  article  of  diet,  is  imperfectly  cured  and  eaten  raw,  poisoning 
from  this  article  of  diet  has  long  been  known.  Other  foods,  as  meats, 
especially  pork  and  fish,  and  vegetable  preparations  sometimes  pro- 
duce alarming  and  even  fatal  illness.  As  a  rule,  the  foods  which  prove 
harmful  are  those  which  have  been  prepared  for  a  relatively  long 
time  before  they  are  eaten.  The  term  "botulism,"  as  here  used,  does 
not  cover  every  form  of  food  poisoning,  but  only  those  in  which  the 
poisonous  substance  is  the  product  of  a  certain  organism.  In  1895 
some  thirty  cases  of  food  poisoning  occurred  in  a  small  Belgian  village 
and  were  investigated  by  Van  Ermengem  of  Ghent.  The  food  in  this 
case  was  a  ham  which  had  been  kept  in  a  dilute  brine.  It  was  from 
a  sound  animal,  a  part  of  which  had  been  eaten  in  the  fresh  state 
without  harm.  In  fact,  the  companion  ham  from  the  same  brine  had 
been  eaten  without  disturbing  those  who  partook  of  it.  The  sound 
piece  lay  near  the  surface  and  was  not  fully  covered  by  the  brine. 
The  faulty  ham  was  on  the  bottom  of  the  vat  and  completely  excluded 
from  the  air.  It  was  not  noticeably  decomposed,  but  was  marked  by 
soft,  colored  spots  and  the  odor  of  butyric  acid.  In  it  the  Bacillus 
botulinus  was  found.  A  watery  extract  from  the  meat  was  injected 
into  various  animals  and  found  to  be  intensely  poisonous.  In  cats, 
it  caused  dilatation  of  the  pupils,  an  abundant  mucus  secretion  in 
the  mouth  and  pharynx,  prolapse  of  the  tongue,  roughness  of  the  voice 
followed  by  complete  aphonia,  difficulty  in  swallowing  and  paralytic 
symptoms,  followed  by  death  in  from  four  to  eight  days.  Mice, 
guinea-pigs,  rabbits  and  apes  were  affected  in  much  the  same  way.  The 
last-mentioned  animals  were  found  to  be  equally  susceptible  when 
fed  with  the  meat  or  its  extract,  while  cats,  rats,  dogs  and  chickens 
were  not  susceptible  by  the  mouth.  Some  five  years  later,  another 
ham  kept  under  similar  conditions  had  a  like  effect  and  contained  the 


138  BOTULISM 

same  organism.  Later  still,  other  small  outbreaks  have  been  studied 
and  the  bacillus  botulinus  found  in  all. 

The  Bacillus. — This  is  a  rod  (from  4  to  6  microns  long  by  0.9  to 
1.2  of  a  micron  broad)  with  imperfectly  rounded  ends.  It  often 
appears  in  chains  formed  of  two  or  more  rods,  attached  end  to  end. 
It  is  slightly  motile,  carrying  from  four  to  eight  flagellae.  It  forms 
spores,  which  for  the  most  part  are  terminal,  rarely  central.  It  takes 
ordinary  stains  easily  and  is  strictly  anaerobic.  In  pure  cultures  it 
will  not  grow  in  the  presence  of  air,  but  in  mixed  cultures  it  may 
do  so,  the  other  organisms  consuming  the  oxygen.  It  develops  gas, 
especially  in  media  containing  grape-sugar  or  other  carbohydrate. 
It  grows  only  feebly  at  the  temperature  of  the  animal  body.  Special 
interest  attaches  to  this  bacillus  because  it  is  not  a  pathogenic,  but 
is  a  toxicogenic  organism.  When  grown  outside  the  body  as  in  the 
ham,  it  elaborates  a  poison  or  toxin  and  it  is  to  this  that  its  harmful 
effects  are  due.  It  causes  not  an  infection,  but  an  intoxication.  When 
all  the  bacilli  have  been  removed  by  filtration  through  porcelain,  the 
clear  filtrate  is  just  as  poisonous  as  the  original  culture.  Indeed,  the 
bacillus  does  not  multiply  in  the  animal  body,  or  does  so  only  to  a 
slight  extent.  Another  very  striking  fact  is  that  the  soluble  poison 
affects  many  animals  when  taken  by  the  mouth.  Most  toxins  and 
venoms  are  harmless  when  introduced  into  the  alimentary  canal,  but 
this  is  not.  One  one-thousandth  of  a  cubic  centimeter,  and  even  a 
smaller  dose,  of  germ-free  filtrate  kills  a  rabbit.  An  effective  anti- 
toxin has  been  prepared  and  used. 

It  is  to  be  remembered  that  it  is  not  this  organism  which  causes 
most  instances  of  food  poisoning,  in  which  nausea,  vomiting,  and 
purging  are  prominent  symptoms.  Bacillus  botulinus  apparently  is 
not  widely  distributed.  So  far  it  has  been  found  only  once  except  in 
food,  and  that  was  in  the  feces  of  hogs.  As  has  been  stated,  it  grows 
only  in  the  absence  of  air  and  it  has  been  found  in  canned  foods.  In 
such,  it  produces  gas  which  bulges  the  ends  of  the  can.  In  brine  of 
more  than  10  per  cent,  strength  it  will  not  grow.  It  is  of  especial 
interest  because  it  is  essentially  a  saprophytic  organism,  producing  in 
food,  in  the  absence  of  air,  a  most  potent  poison  which  affects  man 
when  taken  into  the  stomach. 


CHAPTER    XVII 


MALTA    FEVER 

History. — It  has  long  been  known  that  a  fever  prevalent  on  the 
shores  and  islands  of  the  Mediterranean  differs  from  those  of  other 
regions.  It  is  not  malarial,  nor  typhoid,  nor  typhus.  It  is  a  low,  long- 
continued  fever  with  a  low  mortality  and  characterized  by  a  chronic 
course  accompanied  by  slow  but  progressive  emaciation.  It  has  been 
given  many  names,  such  as  Malta,  Mediterranean,  Cyprus,  Gibraltar 
and  Neapolitan  fever.  It  has  prevailed  extensively  on  the  island  of 
Malta  and  has  afforded  a  field  of  research  for  English  physicians  sta- 
tioned there.  There  have  been  some  differences  of  opinion  as  to 
whether  or  not  it  is  included  among  the  diseases  described  by  Hippo- 
crates. Since  the  means  for  its  positive  identification  have  been  placed 
in  the  hands  of  the  profession,  its  distribution  has  been  found  to  be 
much  wider  than  was  formerly  supposed.  Besides  the  Mediterranean 
shores,  it  has  been  found  in  India,  China,  the  West  Indies,  South 
America,  the  Philippines,  and  in  Texas.  Cases  are  reported  in  most  of 
the  great  ports  of  the  world  among  those  who  have  visited  infected 
regions.  The  specific  cause  was  discovered  by  Bruce  in  1887  in  the 
spleen  of  a  man  who  died  of  the  disease  at  Malta. 

The  Organism. — This  is  known  as  Micrococcus  melitensis  and  is 
one  of  the  smallest  of  the  bacteria,  having  a  diameter  of  about  0.4  of  a 
micron.  It  may  be  seen  as  isolated  bodies,  in  twos,  and  in  chains.  On 
certain  media  it  is  more  ovoid  than  spherical  and  in  this  form  it 
is  regarded  as  a  bacillus.  It  is  non-motile,  save  the  molecular  oscilla- 
tions seen  in  all  small  suspended  bodies,  and  takes  the  ordinary  basic 
aniline  stains  readily  and  deeply.  On  artificial  culture  media  it 
grows  slowly  with  the  temperature  of  the  animal  body  as  its  optimum. 
Under  6  and  above  45  C.  it  does  not  multiply.  It  does  not  liquefy 
gelatin  and  develops  very  slowly  in  this  medium,  requiring  about  five 
days  at  22  to  show  recognizable  colonies.  On  agar  plates  the  colonies 
are  not  always  visible  to  the  unaided  eye  and  when  seen  through  a 


140  MALTA    FEVER 

low  power  appear  much  like  minute  drops  of  water.  It  is  destroyed 
by  moist  heat  in  about  five  minutes  at  60  C.  (140  F.),  with  dry  heat 
at  95  C.  (203  F.)  and  by  direct  sunlight  within  from  a  few  minutes 
to  an  hour  depending  on  the  thickness  of  the  layer  and  the  intensity 
of  the  light.  It  is  quite  highly  susceptible  to  the  usually  employed 
chemical  disinfectants.  However,  in  old  cultures  kept  in  the  dark  it 
may  retain  its  vitality  for  more  than  a  year,  especially  when  complete 
desiccation  is  prevented  by  a  rubber  cap.  In  laboratory  animals  both 
acute  and  chronic  infections  can  be  induced.  For  the  production  of 
the  former  a  relatively  large  inoculation  is  necessary.  The  weight 
begins  to  fall  in  a  few  hours,  then  the  temperature  falls  and  rises.  The 
animal  becomes  weaker,  develops  general  tonic  convulsions  and  at  last 
falls  into  coma  with  low  temperature,  and  dies.  Necropsy  shows  a 
general  septicemia  with  frequent  acute  inflammation  of  the  mucous 
membrane  of  the  urinary  organs. 

The  chronic  form,  after  an  incubation  of  from  two  to  three  days 
develops  a  remittent  or  intermittent  low  fever  with  slow  progressive 
emaciation.  For  months  the  animal  may  seem  quite  well,  save  for  the 
slow,  continued  wasting,  when  it  dies  suddenly.  After  death  most  of 
the  organs  are  found  to  be  sterile,  but  usually  the  coccus  in  small 
numbers  will  be  found  in  the  bone  marrow  or  the  kidneys,  or  in  both. 
Usually  it  is  abundant  in  the  urine  during  the  whole  course  of  the 
disease.  The  spleen  is  generally  found  to  be  markedly  enlarged,  like- 
wise some  of  the  lymphatic  glands. 

Horses,  donkeys,  cattle,  sheep  and  goats  are  susceptible  to  inocu- 
lation. The  study  of  this  infection  in  goats  is  of  special  interest.  In 
these  animals  the  disease  is  exceedingly  chronic  and  seems  to  disturb 
the  animal  but  little.  The  temperature  is  not  altered  and  there  is  not 
always  a  decrease  in  weight.  Frequently  there  is  a  dry  cough.  From 
the  end  of  the  first  to  that  of  the  third  week  the  blood  serum  of  the 
animal  promptly  agglutinates  the  micrococcus.  Indeed,  this  is  the  only 
way  in  which  Malta  fever  can  be  positively  diagnosed  in  either  man  or 
animals.  In  1906  an  English  commission  found  one-third  of  the  goats 
on  the  island  of  Malta  infected  with  this  disease  and  the  micro- 
organism in  the  milk  of  one-tenth.  The  question  of  how  the  goats 
become  infected  naturally  is  an  interesting  one.  Experimentally  this 
is  easily  done  through  an  abrasion  and  it  is  supposed  that  naturally 


MALTA    FEVER  141 

it  occurs  in  the  same  way.  The  hands  of  the  milker,  moist  with  the 
infected  milk  of  one  animal  may  easily  transfer  it  to  another.  The 
udders  of  Malta  goats  are  unusually  large  and  in  some  drag  on  the 
ground.  They  generally  show  slight  wounds,  and  through  these  the 
virus  may  easily  find  its  way  from  the  hands  of  the  milker.  Biting 
flies  have  been  suspected  and  have  been  examined  with  negative 
results. 

Man  and  apes  are  easily  infected  by  feeding.  Of  twenty-eight  apes 
fed  with  infected  milk,  twenty-six  developed  the  disease.  The  course 
is  shorter  and  the  fever  higher  in  apes  than  in  man.  The  milk  of 
infected  goats  is  often  a  pure  culture  of  the  coccus  and  it  may  be  that 
man  occasionally  receives  the  virus  through  minute  wounds ;  the  great 
source  of  infection  is  the  drinking  of  milk.  There  are  several  illus- 
trations of  infection  from  drinking  milk.  In  1905  the  Nicholson  sailed 
from  Malta  with  sixty-five  milk  goats.  The  first  destination  was 
Antwerp.  Of  the  ten  men  who  drank  the  raw  milk  from  the  goats  on 
this  voyage,  eight  developed  Malta  fever  within  from  eighteen  to 
thirty-four  days  after  leaving  Malta.  From  Antwerp  the  Nicholson 
proceeded  to  New  York.  The  captain  and  crew  used  the  goats'  milk 
on  this  trip  and  subsequently  many  of  them  developed  the  disease. 
Five  of  the  goats  died  between  Malta  and  New  York,  and  of  the  sixty 
placed  in  quarantine,  thirty-two  were  shown  to  have  Malta  fever  by 
the  agglutination  test  and  the  coccus  was  found  in  the  milk  of  several. 
In  1910  an  epidemic  of  Malta  fever  appeared  in  the  valley  of  Cavenne 
following  the  importation  of  goats  from  the  island  and  the  use  of 
their  milk.  Malta  fever,  formerly  frequent  among  English  soldiers 
and  sailors  stationed  at  Malta,  has  disappeared  on  the  discontinuance 
of  the  use  of  uncooked  milk  from  goats,  while  it  has  continued  among 
the  natives  who  still  use  the  raw  milk. 


CHAPTER    XVIII 


PNEUMONIA 

History. — As  early  as  1878  Klebs  observed  and  briefly  described 
an  organism  found  in  the  bronchial  content  after  death  from  pneu- 
monia. In  1880  Pasteur  experimented  with  a  micrococcus  found  in 
the  saliva  of  a  boy  under  treatment  for  hydrophobia,  found  it  to  be 
highly  pathogenic  to  rabbits  and  designated  it  microbe  septicemique 
du  salive.  About  the  same  time  Sternberg  gave  an  accurate  descrip- 
tion of  the  morphology  and  pathogenicity  of  an  organism  found  in 
the  saliva  of  healthy  persons.  In  1882-83  Friedlander  studied  the 
sputum  during  life  and  the  bronchial  and  alveolar  contents  after  death 
from  pneumonia  and  found  the  same  organism  that  had  been  seen 
by  others,  and  for  a  time  it  was  known  as  the  capsule  bacillus  or 
Bacillus  Friedlander.  Simultaneously  with  Friedlander,  Talamon  not 
only  observed  the  lanceolate  bacillus,  but  grew  it  in  artificial  media. 
In  1884  A.  Frankel  reported  the  rinding  of  this  organism  in  the  sputum 
of  normal  persons  and  in  that  of  those  suffering  from  pneumonia. 
He  observed  the  great  differences  in  virulence  of  the  strains  obtained 
from  these  sources,  demonstrated  their  effects  on  rabbits  and  mice, 
and,  in  fact,  gave  the  most  complete  report  made  up  to  that  time  on 
the  organism  now  known  as  "Frankel's  bacillus"  or  the  pneumococcus. 
Frankel  in  his  early  papers  held  that  the  pneumococcus  is  the  sole 
cause  of  pneumonia.  Possibly  it  was  this  positive,  but  erroneous, 
statement  which  succeeded  in  fastening  the  name  of  Frankel  to  the 
bacillus.  Certainly  he  was  not  the  first  to  see  it,  or  grow  it,  or  to 
demonstrate  its  effects  on  animals ;  and  he  was  in  error  in  his  claim 
that  it  is  the  sole  cause  of  pneumonia.  Indeed  the  work  done  by 
Weichselbaum  about  the  same  time  was  more  thorough  and,  as  subse- 
quent studies  have  shown,  more  accurate.  The  last  mentioned 
observer  held  that  while  pneumonia  is  usually  caused  by  the  pneumo- 
coccus, it  may  result  from  infection  with  streptococci  and  other  bac- 
teria. This  is  now  generally  recognized. 


144  PNEUMONIA 

The  Bacillus.  —  The  pneumococcus,  known  also  as  Diplococcus 
lanceolatus,  and  Diplococcus  pneumoniae,  is  a  small  lanceolate  organ- 
ism, often  with  spherical  and  ovoid  individuals.  It  presents  marked 
variations  in  shape  and  size,  but  as  a  rule  the  number  of  typical  indi- 
viduals renders  indentification  easy.  It  is  non-motile  and  takes  the 
ordinary  stains  easily.  It  is  a  capsulated  bacillus  and  when  in  diplo- 
coccus  forms,  both  individuals  are  enclosed  by  the  same  capsule.  In 
chain  forms,  not  commonly  seen,  several  links  in  the  chain  may  be 
covered  by  the  same  capsule.  The  formation  of  the  capsule  is  depend- 
ent on  conditions.  Highly  virulent  organisms  taken  from  the  animal 
are  capsulated.  On  the  other  hand,  subcultures  grown  on  artificial 
media  through  many  generations  have  no  capsules  or  show  imper- 
fect ones.  Growth  in  blood  serum  seems  to  favor  capsular  develop- 
ment. It  seems  most  probable  that  the  formation  of  the  capsules  is 
a  protective  function.  The  pneumococcus  grows  on  ordinary  culture 
media,  but  not  abundantly,  and  is  highly  susceptible  to  slight  modi- 
fications in  composition  and  reaction.  Fresh  cultures  do  not  develop 
on  gelatin  below  24  C,  but  old  subcultures  grow  at  temperatures  as 
low  as  20  C.  There  is  no  liquefaction.  After  twenty-four  hours  in 
the  incubator,  bouillon  tubes  are  slightly  cloudy  and  may  show  a 
flocculent  deposit.  As  a  result  of  the  autolysis  of  the  cells  the  bouillon 
may  partially  clear  up  after  some  days.  On  account  of  the  low  spe- 
cific gravity  of  the  cells  a  high  speed  is  necessary  to  completely  deposit 
the  organism  in  a  centrifuge.  On  potatoes  there  is  often  no  growth, 
sometimes  a  slight,  scarcely  visible  coat.  In  milk  this  bacterium 
develops  with  a  scanty  production  of  acid  which  may  suffice  to 
coagulate.  Media  containing  from  4  to  6  per  cent,  of  glycerin  and 
those  containing  blood  or  serum  furnish  richer  growths.  Old  sub- 
cultures develop  on  artificial  media  more  rapidly  and  abundantly 
than  fresh,  virulent  cultures.  Air  supply  has  no  marked  effect,  one 
way  or  the  other,  on  the  growth  of  this  organism.  It  needs  frequent 
transplantation  in  order  to  preserve  both  viability  and  virulence.  It 
is  easily  destroyed  by  the  ordinary  disinfectants,  both  liquid  and 
gaseous. 

There  is  probably  no  other  pathogenic  bacterium  of  such  diver- 
gent virulence  as  this.  I  have  worked  with  two  strains,  one  of  which 
is  fatal  to  guinea-pigs  after  intraperitoneal  injection  only  in  doses  of 


PNEUMONIA  145 

1  c.c.  or  more  of  a  twenty-four-hour  bouillon  culture,  while 
0.0000001  of  this  amount  of  the  other  kills  in  the  same  time. 
The  virulence  may  be  intensified  by  repeated  passage  through  animals, 
but  there  is  great  difference  in  the  degree  with  which  different  strains 
hold  their  virulence.  Some  of  high  power  rapidly  lose  from  gen- 
eration to  generation,  while  others  remain  fairly  steadfast  through 
many  successive  generations.  The  difference  between  strains  of  low 
and  high  virulence  seems  to  be  in  rate  of  multiplication.  Two  guinea- 
pigs  are  treated  at  the  same  time  with  the  two  strains  mentioned 
above.  The  size  of  one  dose  is  0.0000001  that  of  the  other, 
and  still  the  animals  die  at  the  same  time  and  the  growth  in  one  is 
found  after  death  to  be  as  great  as  that  in  the  other.  It  seems  from 
this  that  the  more  virulent  strain  has  multiplied  much  more  rapidly 
than  the  other.  Moreover,  when  large  amounts  of  the  cellular  sub- 
stance of  both  are  obtained  and  split  up  chemically,  the  yield  of  poison 
by  the  two,  per  gram,  is  the  same.  This  certainly  is  strong  evidence 
that  difference  in  virulence  is  determined  by  rate  of  growth. 

While  the  pneumococcus  is  quite  labile  in  structure,  under  certain 
conditions,  it  easily  undergoes  autolysis  and  is  destroyed  quickly  by  dis- 
infectants. Samples  of  sputum  have  been  found  to  retain  virulent 
cocci  for  months.  All  sputum  should  be  burned  or  otherwise  destroyed. 
Floors  and  sidewalks  are  not  proper  receptacles  for  expectoration  from 
either  the  well  or  the  sick. 

It  is  a  matter  of  scientific  interest  that  bile  not  only  destroys  but 
dissolves  living,  virulent  pneumococci.  On  dead  and  non-virulent 
cultures  bile  has  no  such  action.  This  solvent  effect  has  been  found 
to  be  due  to  the  bile  acids.  Since  most  other  pathogenic  bacteria 
easily  multiply  in  undiluted  bile,  this  effect  on  pneumococci  is  striking 
and  interesting,  although  it  is  not  known  to  be  of  any  practical 
importance. 

The  laboratory  animals  most  susceptible  to  the  pneumococcus  are 
the  rabbit  and  the  mouse.  Fresh  cultures  in  bouillon  containing  10 
per  cent,  of  ox  serum  kill  these  animals  on  subcutaneous  or  intraperi- 
toneal  inoculation  in  doses  as  small  as  0.0000001  c.c.  However,  animals 
thus  treated  do  not  develop  pneumonia,  but  die  of  general  septicemia. 
It  has  been  found  by  examination  of  the  sputum  and  by  lung  puncture 
that  the  virulence  of  the  coccus  abates  day  by  day  as  the  disease 


146  PNEUMONIA 

develops.  Pulmonary  hepatization  has  been  induced  in  rabbits  by 
tracheal,  intrapleural  and  intrapulmonary  inoculations  with  less  viru- 
lent cultures.  Rats  are  but  little  less  susceptible  than  rabbits  and 
mice,  then  follow  guinea-pigs,  dogs,  cats  and  sheep.  In  the  less  sus- 
ceptible animals  local  lesions  are  more  common  than  in  the  more 
highly  susceptible.  This  raises  the  question  of  the  relative  susceptibility 
of  man.  It  is  reasonable  to  suppose  that  man  is  quite  refractory,  com- 
pared with  rabbits  and  mice,  to  the  pneumococcus.  He  generally  carries 
the  organism  in  his  mouth,  but  becomes  infected  with  it  only  under 
certain  conditions.  It  does  not  induce  a  general  septicemia  in  man. 
Klemperer  has  shown  that  a  culture  highly  virulent  to  rabbits  is  fol- 
lowed by  only  a  local  reaction  when  injected  subcutaneously  in  man. 
Spontaneous  and  epidemic  pneumonia  has  been  observed  in  guinea- 
pigs  and  the  disease  has  been  induced  in  these  animals  by  inhalation 
and  by  intratracheal  and  intrapulmonary  inoculations.  The  pneumonia 
thus  induced  may  be  either  acute  or  chronic.  It  often  involves  several 
lobes  and  presents  the  anatomic  characteristics  of  a  catarrhal  rather 
than  a  croupous  process.  It  is  generally  fatal. 

The  question  of  the  production  of  a  toxin  by  the  pneumococcus  has 
been  the  basis  of  much  experimental  work.  The  evidence  supplied  by 
these  experiments  seems  to  show  quite  conclusively  that  this  organism 
elaborates  or  secretes  no  true  toxin  like  that  of  the  diphtheria  bacillus, 
but  like  all  bacterial  proteins  it  does  yield  a  poison  when  properly 
disrupted.  When  suspended  in  salt  solution  the  cells  easily  and  quickly 
undergo  autolytic  changes  whereby  a  poison  is  liberated.  This  has 
been  conclusively  demonstrated  by  the  work  of  Rosenow  and  others. 

That  a  certain  degree  of  active  immunity  to  this  organism  can  be 
established  in  rabbits  and  other  animals  seems  to  have  been  demon- 
strated. For  this  purpose,  heated  sputum,  heated  cultures,  cultures 
attenuated  by  phenol,  cocci  dissolved  in  bile,  and  the  residue  left  after 
autolysis  have  been  employed.  One  attack  of  the  disease  in  man 
confers  at  least  no  lasting  immunity,  and  often  appears  to  render  the 
individual  more  susceptible.  That  the  sera  of  immunized  animals 
have  some  protection  and  even  some  curative  value  in  the  disease  in 
both  man  and  animals  seems  to  be  demonstrated,  but  that  such  sera 
have  true  antitoxic  values  is  certainly  not  demonstrated.  Some  claim 
that  the  sera  of  immunized  animals  have  a  bactericidal  action, 


PNEUMONIA  147 

while  others  think  that  they  only  render  phagocytic  action  more  effec- 
tive. The  best  pneumococci  sera  either  in  the  fresh  state  or  after 
the  addition  of  complement  do  not  destroy  the  organism.  They  may 
possibly  stimulate  the  phagocytes  or  they  may  render  the  cocci  more 
susceptible  to  the  phagocytes.  In  order  to  be  of  service  either  in 
prevention  or  treatment,  a  relatively  large  amount  of  the  immune 
serum  must  be  used.  In  other  words,  a  certain  degree  of  concentra- 
tion must  be  reached.  The  law  of  multiple  proportions  which  holds 
good  between  diphtheria  toxin  and  antitoxin  fails  here.  Some  have 
found  that  the  immune  sera  which  they  have  studied  are  effective 
only  against  those  strains  used  in  immunizing  the  animals  and  this 
view  has  induced  attempts  to  secure  polyvalent  sera,  but  up  to 
the  present  time  these  cannot  be  pronounced  successful. 

Neufeld  and  Handel,  in  a  discussion  of  the  value  of  pneumococci 
sera,  conclude  that  experiments  on  animals  have  shown  that  such 
have  not  only  a  protective  but  a  curative  effect  on  both  septicemic 
processes  and  pneumonia,  but  not  until  the  dose  is  large  enough  to 
reach  a  certain  concentration  in  the  body. 

Some  of  the  strongest  opponents  of  the  phagocytic  theory  admit 
that  natural  immunity  to  this  disease  is  due  to  phagocytic  action  and 
that  extracellular  destruction  of  the  pneumococcus  has  not  been  dem- 
onstrated. Furthermore,  they  state  that  even  normal  serum  in  large 
doses  protects  animals  against  this  infection. 

Inasmuch  as  a  large  proportion  of  healthy  people  carry  the  pneumo- 
coccus in  their  mouths  and  throats,  the  question  of  what  happens  when 
one  develops  the  disease,  becomes  one  of  both  practical  and  scientific 
interest.  Several  possibilities  suggest  themselves.  In  the  first  place, 
while  this  organism  is  found  in  most  cases  of  lobar  pneumonia,  it  is 
not  found  in  all  instances.  Moreover,  while  frequently  present  in 
other  forms  of  pneumonia,  it  is  not  so  constantly  present  in  these. 
The  best  of  evidence  exists  for  the  statement  that  true  croupous 
pneumonia  may  be  due  to  other  bacteria,  such  as  the  pneumobacillus, 
Streptococcus  pyogenes  and  Streptococcus  mucosus.  These  facts  have 
led  some  to  believe  that  pneumonia  may  be  due  to  the  conjoint  activity 
of  two  or  more  organisms,  but  no  two  of  these  are  constantly  found 
and  there  seems  to  be  no  substantial  basis  for  this  idea.  A  second 
possibility  is  that  the  pneumococcus  normally  present  in  the  saliva 


148  PNEUMONIA 

does  not  cause  pneumonia  and  that  the  disease  results  only  when  one 
harbors  a  more  virulent  strain.  Those  who  hold  to  this  theory  insist 
that  disinfection  of  all  pneumonia  sputum  and  the  isolation  of  those 
suffering  from  this  disease  should  be  rigidly  enforced.  Opponents  of 
this  theory  point  out  that  such  measures  do  not  lead  to  a  decrease  in 
the  prevalence  of  this  disease.  They  say  that  while  isolation  and  dis- 
infection are  followed  by  a  decrease  in  other  infectious  diseases,  they 
have  had  no  such  effect  on  pneumonia.  A  third  possibility  is  that 
the  pneumococcus  so  constantly  the  guest  of  man,  becomes  virulent 
when  for  any  reason  the  vitality  of  the  individual  is  lowered.  To-day 
this  is  the  prevalent  belief  and  it  must  be  added  that  it  has  much  sup- 
port. The  frequency  with  which  pneumonia  develops  after  exposure 
to  cold  is  generally  admitted.  That  form  of  pneumonia  which  follows 
injury  to  the  lung  tissue,  known  as  traumatic  pneumonia,  and  the  fre- 
quency and  the  great  fatality  of  this  disease  among  chronic  alcoholics 
and  in  the  general  enfeeblement  of  old  age  are  illustrations.  The  safest 
plan  is  to  isolate  the  pneumonia  patient,  to  disinfect  his  expectoration, 
and  to  avoid  all  conditions  which  render  the  body  more  susceptible  to 
this  and  other  bacteria,  which  may  cause  this  disease.  However,  it 
must  be  added  that  the  epidemic  character  frequently  exhibited  by 
pneumonia  leaves  no  doubt  in  my  mind  that  exposure  to  an  unusually 
virulent  strain  of  the  pneumococcus  is  an  important  factor  in  the 
distribution  of  this  disease. 


CHAPTER    XIX 


TETANUS 

History. — A  disease  with  such  striking,  distressing  and  fatal  symp- 
toms, as  those  characteristic  of  lockjaw,  could  scarcely  escape  observa- 
tion and  comment  whenever  seen.  It  is  not,  therefore,  surprising  that 
the  medical  records  of  Greece  and  Rome  supply  details  of  the  symptoms 
and  notes  of  the  great  fatality  of  this  disease.  However,  in  all  ages 
it  has  been  relatively  rare  except  in  certain  restricted  localities.  It  was 
a  matter  of  early  record  that  tetanus  was  in  some  way  connected 
with  wounds.  It  was  seen  to  be  more  common  in  military  than  in 
civil  life  and  in  the  latter  it  most  frequently  follows  injury.  Before 
the  development  of  experimental  medicine,  theories  concerning  the 
causation  of  this  disease  were  many  and  diversified.  It  was  soon 
seen  that  while  it  generally  followed  injuries,  it  did  not  follow  all,  and 
that  there  was  no  relation  between  the  severity  and  extent  of  the  injury 
and  the  development  of  tetanus.  The  infectious  nature  of  the  disease 
was  first  emphasized  by  French  physicians,  especially  Verneuil.  How- 
ever, the  first  positive  demonstration  of  its  infective  character  was 
made  in  1884  by  two  Italian  physicians,  Carle  and  Rattone,  who  inocu- 
lated twelve  rabbits  with  matter  taken  from  an  acne  pustule  on  a  man 
with  tetanus.  Within  two  or  three  days,  eleven  of  the  animals  thus 
treated  developed  the  disease.  Furthermore,  they  succeeded  in  trans- 
ferring the  infection  to  other  animals.  Soon  thereafter,  Nicolaier 
induced  tetanus  in  rabbits,  guinea-pigs  and  mice  by  inserting  bits  of 
earth  under  the  skin.  He  also  found  the  specific  bacillus  and  grew  it 
in  mixed  cultures,  but  failed  to  separate  it  from  associated  bacteria. 
This  was  done  by  Kitasato. 

The  Bacillus. — Kitasato  found  that  the  tetanus  bacillus  grows  only 
when  the  air  is  excluded  and  that  it  forms  spores  which  are  markedly 
resistant  to  high  temperature.  He  smeared  the  infected  material  on 
agar,  kept  the  tubes  at  incubator  temperature  for  two  days,  the  time 
required  for  the  bacilli  to  develop  spores  abundantly,  and  then  heated 


150  TETANUS 

at  80  C.  for  one  hour  and  allowed  the  spores  which  had  withstood 
this  temperature  to  develop  in  an  atmosphere  of  hydrogen.  The  high 
temperature  killed  all  the  bacilli,  both  those  of  tetanus  and  other  kinds 
present,  but  did  not  destroy  the  tetanus  spores.  The  bacillus  is  a 
rod,  from  2  to  4  microns  long  and  from  0.3  to  0.5  of  a  micron  broad. 
It  is  feebly  motile,  carrying  numerous  flagellae  and  is  often  found 
in  chains.  The  bacilli  develop  terminal  spores,  spherical  or  oval  bodies, 
with  a  diameter  larger  than  the  breadth  of  the  bacillus.  This  gives 
to  the  spore-bearing  orgainsm  a  drum-stick  appearance.  It  is  a 
liquefying  organism  and  takes  the  ordinary  stains  easily  and  distinctly. 
It  is  strictly  anaerobic,  which  accounts  for  the  fact  that  the  disease 
develops  most  frequently  in  deep  wounds  with  closed  openings  and 
rarely  in  those  in  which  the  infecting  material  is  freely  exposed  to 
the  air.  Tetanus  spores  are  among  the  most  resistant  forms  of  bac- 
terial life.  A  splinter  of  wood  bearing  infected  material  may  remain 
a  source  of  danger  for  many  years.  Direct  sunlight  kills  the  spores 
within  from  two  hours  to  many  days,  depending  on  the  thickness  of 
the  layer  and  the  intensity  of  the  light.  They  are  destroyed  by  live 
steam  within  five  minutes;  by  5  per  cent,  phenol  after  fifteen  hours; 
by  mercury  chlorid  (1 :  1000)  after  three  hours. 

Tetanus  spores  are  widely  and  unevenly  distributed  over  the  earth. 
In  some  localities  100  per  cent,  of  animals  inoculated  with  earth 
develop  the  disease,  while  in  other  places  such  inoculations  wholly 
fail.  As  a  rule  the  spores  are  most  abundant  in  filthy  soil,  especially 
that  impregnated  with  manure.  Before  the  days  of  aseptic  surgery, 
tetanus  was  especially  prone  to  follow  operative  procedures  as  was 
noted  by  Larrey,  Napoleon's  great  surgeon,  and  many  other  operators 
both  in  the  field  and  in  the  hospital.  Among  certain  primitive  and  dirty 
people  tetanus  of  the  newly  born  is  frequent  on  account  of  the  methods 
of  cutting  and  dressing  the  cord.  On  certain  islands,  as  Reunion  and 
Cayenne,  the  infantile  death-rate  from  this  cause  has  in  some  years 
been  as  high  as  50  per  cent.  In  other  localities  tetanus  works  havoc 
among  women  in  the  puerperal  state.  Some  savage  tribes  smear 
their  arrowheads  with  mud  rich  in  tetanus  spores.  The  marked  mortal- 
ity from  Fourth  of  July  celebrations  in  this  country  a  few  years  ago 
was  due  to  tetanus  infection.  Fortunately,  the  barbaric  rites  with 
which  we  were  accustomed  to  celebrate  the  birthday  of  our  nation 


TETANUS  151 

have  been  beneficially  modified,  largely  through  the  knowledge  spread 
by  The  Journal  of  the  American  Medical  Association.  The  parts  of 
our  country  most  abundantly  infected  with  this  virus  seem  to  be  the 
Atlantic  States,  Long  Island  and  the  valley  of  the  Hudson.  Commer- 
cial gelatin  and  catgut  used  by  surgeons,  have  been  the  bearers  of 
this  infection  and  most  thorough  sterilization  is  necessary  in  order 
to  destroy  the  spores.  Formerly,  we  spoke  of  idiopathic  and  traumatic 
tetanus.  Now,  we  are  quite  sure  that  the  former  does  not  exist. 
The  wound  may  be  so  trivial  that  it  has  healed  before  symptoms  of 
tetanus  develop.  In  other  cases  the  wound  may  be  not  on  the  skin 
but  on  a  mucous  membrane  as  in  the  mouth,  nose  or  throat.  I  saw  a 
case  in  which  the  virus  had  entered  through  the  gum  from  which  a 
tooth  had  been  extracted.  Some  have  claimed  that  tetanus  is  more 
prevalent  in  black  and  mixed  races  than  among  whites  and  have 
endeavored  to  show  the  existence  of  racial  susceptibility.  The  truth 
is  that  filthiness  is  the  predisposing  agent  rather  than  a  racial  difference. 
The  simple  custom  of  drying  the  wash  by  spreading  the  clothes  on  the 
ground  has  been  found  to  play  a  part  in  the  prevalence  of  this  disease. 

The  distribution  of  the  tetanus  virus  seems  to  be  world  wide.  It  has 
been  found  in  every  land  and  in  many  waters,  such  as  those  of  Lake 
Geneva  and  the  Dead  Sea.  It  may  be  present  in  bilge  water  and 
ships  may  be  generally  infected.  On  one  English  ship,  after  a  naval 
battle,  sixteen  of  the  wounded  died  of  tetanus.  It  may  be  carried 
into  wounds  with  bits  of  infected  clothing,  and  it  has  been  found  on 
nearly  every  article  worn  by  soldiers  from  the  shoes  to  collars.  Virgin 
forest  soil  has  generally  been  found  free  from  this  virus,  but  the 
sweepings  from  the  streets,  stables,  houses,  boats  and  cars  frequently 
produce  tetanus  when  introduced  under  the  skin  of  animals. 

Of  our  domestic  animals,  the  horse  is  the  most  susceptible  and 
is  a  frequent  victim.  The  ox  comes  next  on  the  list,  followed  closely 
by  sheep  and  goats.  Dogs  and  cats  are  not  easily  infected,  but  do 
succumb  to  inoculations. 

When  swallowed  the  tetanus  bacillus  has  no  effect  .unless  there  be 
some  break  in  the  mucous  membrane,  and  it  is  eliminated  with  the 
feces  unchanged.  In  this  way  the  fecal  matter  of  man  and  animals 
pollutes  the  soil.  The  tetanus  bacillus  produces  a  soluble  toxin  which 
is  one  of  the  most  potent  poisons  known.  Injected  into  an  animal, 


152  TETANUS 

even  in  a  dose  of  a  fraction  of  a  milligram,  it  develops  tetanus  after  a 
period  of  incubation  of  a  few  days.  Great  care  should  be  used  in  the 
employment  of  vaccines  and  sera  for  fear  of  inoculation  with 
tetanus.  The  vaccine  may  carry  the  infection  or  it  may  be  introduced 
later  through  the  vaccine  lesion.  Such  an  accident  occurred  at  Camden, 
New  Jersey,  in  1901,  when  several  children  vaccinated  against  small- 
pox developed  tetanus  and  died.  A  similar  misfortune  was  reported 
from  India  in  1902.  Out  of  a  group  of  107  persons  vaccinated  against 
plague,  nineteen  died  of  tetanus.  In  St.  Louis,  diphtheria  antitoxin 
was  drawn  from  a  horse  which  was  apparently  well,  but  which  devel- 
oped tetanus  a  fe  wdays  later.  Some  of  the  children  treated  for 
diphtheria  with  this  serum  died  of  tetanus. 


CHAPTER    XX 


STREPTOCOCCIC    INFECTION 

History. — The  streptococcus  probably  has  a  much  longer  ancestry 
than  man  and  began  its  assaults  on  the  animal  kingdom  long  before 
there  was  any  indication  of  the  development  of  homo  sapiens.  The 
unicellular  has  been  the  companion  of  the  multicellular  through  all  the 
evolutionary  forms  of  the  latter.  Man  came  into  existence  as  a  host 
to  the  streptococcus  and  the  victims  of  the  microscopic  parasite  are  as 
innumerable  as  the  sands  of  the  seashore.  Borne  on  the  surface  and 
in  the  cavities  of  the  greater,  the  smaller  has  always  been  ready  to 
find  its  way  into  the  vitals  of  its  host  and  to  feed  on  blood  and  tissue 
until  the  whole  became  its  prey.  In  peace  and  in  war,  among  the 
good  and  the  bad,  the  wise  and  the  foolish,  the  streptococcus  has  always 
been  a  factor  in  determining  the  mortality  rates.  As  a  primary  infec- 
tion there  is  no  part  of  man's  anatomy  immune  to  the  invasion  of  this 
organism.  As  a  secondary  infection,  it  profits  by  the  lesions  induced 
by  other  pathogenic  bacteria.  As  a  terminal  infection,  it  swarms  over 
every  part  of  dying  man,  and  secures  the  greater  part  of  the  booty  of 
every  war,  whether  waged  by  itself  as  principal,  as  ally  or  as  guerilla. 
In  the  earliest  medical  records  wound  infection  is  described.  It  became 
the  scourge  of  armies  and  the  military  hospital  was  often  more  dreaded 
and  more  deadly  than  the  field  of  battle.  Indeed,  there  was  a  time 
when  all  hospitals,  both  military  and  civil,  became  great  incubators 
for  the  growth  and  dissemination  of  pus  germs.  In  the  old  Hotel  Dieu 
at  Paris,  the  simplest  amputations  were  followed  by  infection  and  in 
a  large  number  this  terminated  only  in  death.  Even  after  the  dis- 
covery of  surgical  anesthesia,  when  operations  were  no  longer  forms 
of  torture,  wound  infection  remained  the  horrid  nightmare  of  the 
surgeon.  Happily  the  science  of  Pasteur  and  its  application  to  surgery 
by  Lister,  opened  a  new  era  in  the  history  of  surgery.  In  the  first  half 
of  the  nineteenth  century,  Gaspard,  Leurent  and  others  taught  that 
wounds  become  infected  with  invisible  organisms,  but  this  was  only 


154  STREPTOCOCCIC    INFECTION 

theory  and  at  that  time  impossible  to  demonstrate.  Pasteur  undoubt- 
edly in  some  of  his  early  work  saw  pus  organisms,  but  the  credit  of 
identifying  and  describing  them  belongs  to  Ogston,  who  found  that 
some  are  spherical  bodies  arranged  in  chains  while  others  are  clustered 
like  grapes  in  a  bunch.  The  former  he  designated  streptococci  and  the 
latter  staphylococci. 

The  Organism. — Streptococci  are  spherical  or  oval  bodies,  from 
0.5  to  1.5  of  a  micron  in  diameter,  arranged  in  chains  of  variable  length. 
Some  strains  show  only  short,  and  others  only  long,  chains.  Some 
investigators  regard  these  as  different  species,  while  others  consider 
them  as  only  varieties.  It  seems  most  reasonable  to  look  on  the 
streptococci  as  a  great  family  with  many  subfamilies,  and  these  may 
show  marked  differences  in  form,  in  cultural  characteristics,  and  in 
virulence.  All  are  non-motile  and  sporeless.  Inasmuch  as  these  organ- 
isms induce  suppuration,  they  are  often  designated  as  Streptococci 
pyogenes,  to  which  we  may  add  longus  or  brevis,  as  the  case  may  be. 
Some  authors  divide  them  according  to  the  tenacity  with  which  they 
cling  together  or  the  amount  of  mucus  formed,  thus  providing  a  type 
known  as  5.  mucosus.  In  the  animal  body  the  chains  are  generally 
short,  often  being  reduced  to  diplococci.  In  artificial  cultures  the 
chains  are  often  long  and  coiled  in  groups  forming  felt-like  masses. 
Cultures  rich  in  peptone  (as  high  as  5  per  cent.)  give  the  most 
abundant  growths.  The  presence  of  grape-sugar  (from  0.2  to  2  per 
cent.)  favors  growth,  but  the  development  of  too  much  acid  may  prove 
detrimental.  Blood  serum,  either  alone  or  in  bouillon,  is  an  excellent 
medium,  and  strains  obtained  from  man  grow  best  on  human  serum, 
and  the  same  holds  good  for  other  species.  The  streptococcus  does  not 
grow  abundantly  on  ordinary  solid  media.  The  optimum  temper- 
ature is  that  of  the  animal  body,  but  growth  proceeds  slowly  at  as  low 
as  15  and  as  high  as  42  C.  The  streptococcus  is  a  facultative  anaerobe, 
but  different  strains  show  wide  variations  under  diverse  air  supply. 
In  general,  however,  in  the  presence  of  air  this  organism  loses  in  both 
viability  and  virulence.  Different  strains  act  differently  on  carbo- 
hydrates and  attempts  at  classification  have  been  made  on  this  basis, 
but  have  led  to  no  practical  results.  These  are  varieties  which  decom- 
pose lactose  and  coagulate  milk.  A  striking  action  is  the  hemolytic  effect 


STREPTOCOCCIC    INFECTION  155 

of  streptococci  cultures.  The  capability  of  dissolving  red  corpuscles 
was  first  noted  by  Marmorek  in  1895,  and  has  been  the  subject  of 
much  study  since  that  time.  If  a  tube  of  bouillon  to  which  0.5  c.c.  of 
blood  has  been  added  be  inoculated  with  the  streptococcus  and  incu- 
bated, in  a  few  hours  the  corpuscles  are  completely  dissolved,  coloring 
the  whole  fluid.  On  prolonged  standing,  the  color  becomes  brown, 
owing  to  the  conversion  of  oxyhemoglobin  into  methemoglobin.  It  was 
at  first  thought  that  the  hemolytic  action  is  due  directly  to  the  living 
organism,  but  Besredka  showed  that  germ-free  filtrates  of  highly 
active  cultures  are  hemolytic.  The  hemolytic  substance  is  highly  labile 
and  is  destroyed  by  a  temperature  of  60  C.  It  must  be  classed  as  a 
ferment.  Indeed,  it  seems  that  there  are  two  ferments,  one  of  which 
dissolves  the  corpuscles,  while  the  other  converts  the  soluble  oxyhemo- 
globin into  methemoglobin.  Although  this  organism  is  sporeless,  it 
may  not  only  live  but  retain  its  virulence  for  many  months  in  cool, 
dark  places.  Before  the  days  of  aseptic  surgery,  certain  wards  in 
hospitals  became  infected  with  erysipelas  and  retained  the  infection 
through  long  periods.  Puerperal  fever  followed,  or  rather,  accom- 
panied, certain  midwives  and  obstetricians  from  house  to  house  until 
they  came  to  believe  that  some  dreadful  fate  hung  over  them  and  in 
despair  fled  from  those  who  sought  their  services.  Holmes  collected 
cases  of  this  kind  and  concluded  that  puerperal  fever  and  other  forms 
of  sepsis  are  due  to  a  contagium.  The  experiences  of  Semmelweis  in 
the  old  lying-in  wards  at  Prague  led  him  to  the  same  conclusion,  and  he 
pointed  out  that  the  obstetrician  could  not,  with  safety  to  those  under 
his  charge,  go  from  the  dead  room  to  the  woman  in  labor  without  first 
making  himself  clean.  Moreover,  he  demonstrated  in  his  own  work 
that  cleanliness  on  the  part  of  the  accoucheur  resulted  in  the  reduction 
of  the  number  of  cases  of  puerperal  fever. 

The  streptococcus  freshly  taken  from  an  infected  man  is  not  highly 
pathogenic  to  laboratory  animals.  Large  doses  are  necessary  to  fatal 
infection  and  subcutaneous  inoculations  usually  induce,  at  most,  local 
abscesses.  When  mice  are  inoculated  at  the  root  of  the  tail,  the  organ- 
ism multiplies  at  the  point,  spreads  through  the  connective  tissue  and 
finally  is  carried  by  lymph  and  blood  to  various  organs,  and  death  may 
result  in  three  or  four  days,  earlier  with  the  most  virulent  strains. 
With  less  virulent  cultures  a  local  abscess  may  develop  and  continue 


156  STREPTOCOCCIC    INFECTION 

active  for  weeks,  during  which  time  there  is  a  slowly  progressive 
emaciation.  Intraperitoneal  injections  induce  fatal  peritonitis.  Ani- 
mals have  been  infected  by  feeding  experiments.  In  such  cases  the 
primary  infection  develops  in  the  small  intestine,  causing  an  acute 
enteritis  and  followed  by  systemic  infection  and  death.  Repeated 
passage  through  animals  rapidly  increases  the  virulence  and  in  this 
way  cultures  have  been  obtained  which  kill  rabbits  in  doses  of 
0.0000001  c.c.  However,  not  all  strains  can  be  developed  to  this 
extent.  Association  with  certain  other  bacteria,  such  as  the  proteus 
and  colon  bacillus,  is  favorable  to  an  increase  in  virulence.  The  pres- 
ence of  bile  seems  to  have  a  like  effect.  The  condition  of  the  animal 
influences  the  rate  of  increase  in  virulence.  Starvation,  overexertion, 
and  other  depressing  influences  render  the  animal  more  susceptible. 
The  same  is  true  of  the  condition  of  the  infected  tissue.  Extensive 
bruises,  lacerations,  and  other  injuries  favor  the  growth  of  the  strepto- 
coccus. When  implanted  on  a  mucous  membrane  already  irritated 
by  chronic  catarrh,  scarlet  fever,  or  diphtheria,  this  micro-organism 
multiplies  with  unusual  rapidity  and  develops  marked  virulence.  Each 
species  of  animal  seems  to  have  its  own  strain  of  streptococcus.  The 
bacterium  accommodates  itself  to  its  peculiar  host  and  thrives  best 
on  that  species.  Those  strains  found  on  man  are  more  pathogenic  to 
man  than  those  found  on  other  animals,  and  when  the  virulence  of 
any  strain  is  increased  by  repeated  passage  through  a  certain  animal, 
it  is  more  pathogenic  to  that  than  to  other  species. 

There  is  no  tissue  or  organ  of  the  human  body  immune  to  invasion 
by  this  organism.  When  a  virulent  strain  of  the  streptococcus  finds  its 
way  into  the  lymph  vessels  of  the  skin,  erysipelas  results.  There  is 
marked  migration  of  leukocytes  to  the  infected  area,  which  becomes 
red  and  swollen  and  extends  more  or  less  rapidly.  When  experi- 
mentally induced,  the  period  of  incubation  varies  from  ten  to  sixty 
hours.  The  injury  done  depends  on  the  virulence  of  the  infecting 
strain  and  may  be  slight  and  superficial  or  it  may  be  widely  destructive 
and  fatal.  The  infection  may  extend  to  mucous  surfaces,  to  internal 
organs  and  to  the  brain  and  its  membranes.  A  case  of  erysipelas  does 
not  necessarily  come  from  a  preceding  case  of  the  same  disease,  for 
the  infection  may  be  transferred  from  any  pyemic  or  septic  source 
to  the  skin.  Erysipelas  may  be  acquired  from  puerperal  fever  or 


STREPTOCOCCIC    INFECTION  157 

the  reverse  may  be  true.  This  was  suspected  long  before  we  had  any 
definite  knowledge  of  bacteria.  The  village  doctor  of  that  time  knew 
that  it  was  not  a  wise  thing  to  attend  a  childbirth  while  he  had  patients 
with  erysipelas  or  scarlet  fever,  or  while  he  was  dressing  infected 
wounds.  This  indefinite  knowledge  of  that  time  has  been  defined 
by  experiments.  Erysipelas  has  been  induced  experimentally  with 
matter  taken  from  wounds,  from  throats  in  angina,  and  from  the 
uterus  in  puerperal  fever.  All  these  and  many  other  diseases  are  due 
to  the  same  organism  and  are  mutually  convertible  one  into  another. 

When  the  infection  lies  deeper  and  in  the  subcutaneous  tissue, 
diffuse  phlegmon  and  widely  extended  abscesses  with  extensive 
destructive  changes  result.  With  the  infection  in  the  larger  lymph 
vessels,  lymphangitis  and  lymphadenitis  occur.  In  these  either  the 
streptococcus  or  the  staphylococcus,  or  both,  may  be  found.  Other 
skin  affections  due  to  the  pus  bacteria  are  acne,  impetigo,  erythema 
and  infectious  purpura.  From  infected  wounds  a  scarlatinous  rash 
may  extend  over  the  greater  part  of  the  body,  and  may  lead  to  arthritis 
and  nephritis. 

The  streptococcus  is  frequently  found  in  every  part  of  the  respira- 
tory passages  and  it  seems  to  play  an  important  role  in  various  inflam- 
matory diseases  of  these  parts.  Whether  the  normal  residents  of  these 
surfaces  become  suddenly  virulent  or  more  virulent  strains  are  intro- 
duced, is  not  always  easily  determined.  The  streptococcic  sore  throat, 
which  has  in  recent  years  occurred  in  epidemic  form  and  proved  so 
highly  fatal,  is  believed  to  be  due  to  the  use  of  milk  containing  highly 
virulent  strains.  There  are  reasons  for  believing  that  the  essential,  if 
not  the  sole,  causal  factor  in  scarlet  fever  is  a  streptococcus.  This 
organism  is  found  constantly  in  otitis  media.  Malignant  endocarditis 
and  polyarthritis  are  due  to  virulent  strains  of  the  streptococcus. 
Streptococcic  pneumonia  is  recognized  and  may  run  either  an  acute  or 
a  chronic  course.  The  latter  may  resemble  typhoid  fever  and  the 
intensity  of  the  general  symptoms  may  be  out  of  proportion  to  the 
physical,  local  findings.  Purulent  pleurisy  is  not  rare.  The  part  taken 
by  the  streptococcus  in  the  etiology  of  the  summer  diarrheas  of  infancy 
seems  to  be  important  and  market  milk  often  contains  virulent  strains 
of  this  organism.  In  inflammatory  diseases  of  the  udders  of  cows, 
highly  active  strains  of  the  streptococcus  find  their  way  into  the  milk. 


158  STREPTOCOCCIC    INFECTION 

In  other  cases  the  organism  in  the  tonsils  of  the  child  may  pass  into 
the  intestine  and  induce  a  serious  enteritis.  From  the  intestine  the 
organism  may  pass  into  the  blood  and  a  systemic  infection  may  result. 
In  such  cases  the  streptococcus  has  been  found  not  only  in  the  stools, 
but  in  the  blood  and  urine  also. 

The  secretions  of  the  vagina,  in  both  pregnant  and  non-pregnant 
women,  often  contain  streptococci,  but  for  the  most  part,  at  least,  these 
are  not  numerous  and  are  non-virulent.  This  is  due  to  the  fact  that 
under  normal  conditions  the  vaginal  tract  is  self-cleaning  and  its 
secretions  are  bactericidal.  In  the  puerperal  state,  when  bits  of  pla- 
centa or  membrane  are  left  in  the  uterus,  the  streptococci  normally 
present  may  become  virulent  and  may  lead  to  a  septic  condition.  It 
is  possible,  therefore,  for  puerperal  fever  to  develop  without  extrane- 
ous infection.  That  this  is  not  the  usual  way  in  which  puerperal  fever 
originates  is  quite  certain.  A  virulent  strain  is  introduced  shortly 
before,  during  or  after  labor.  It  may  happen  before  labor  by  vaginal 
examination,  by  improper  douches  or  by  coitus.  It  may  happen  during 
labor  by  some  fault  of  the  accoucheur.  It  may  happen  after  labor  by 
improper  douches  or  handling  the  parts.  The  obstetrician  must  guard 
against  both  autogenous  and  exogenous  infection.  He  must  avoid 
those  conditions  which  tend  to  increase  the  virulence  of  organisms 
normally  present  and  he  must  prevent  the  introduction  of  virulent 
cocci.  Puerperal  fever  is  not  confined  to  the  human  species,  but 
occurs  in  cows  and  other  domestic  animals.  Contagious  coryza,  the 
pleuropneumonia  of  horses,  and  certain  inflammatory  diseases  of  the 
udders  of  cows,  are  results  of  streptococcic  infection.  Moreover, 
wound  infection  and  sepsis  are -frequent  causes  of  death  among  all  the 
higher  animals. 

The  streptococcus  does  not  produce  a  soluble  toxin  in  the  sense 
of  that  elaborated  by  the  diphtheria  bacillus.  Its  hemolytic  product 
is  a  soluble  toxin,  but  the  poisonous  agent  in  the  cellular  substance  of 
streptococci  is  the  protein  poison.  Filtrates  from  old  cultures  in  large 
doses  kill  animals,  but  there  is  nothing  specific  in  this.  Marmorek  grew 
cultures  in  blood  serum  for  three  months  and  found  that  the  filtrate 
killed  animals,  but  the  same  result  may  be  accomplished  with  many 
non-pathogenic  organisms.  Baginsky  and  Sommerf eld  grew  the  organ- 
ism in  strongly  alkaline  bouillon  cultures  for  many  weeks  and  found 


STREPTOCOCCIC    INFECTION  159 

that  the  filtrate,  in  doses  of  5  c.c.  intravenously,  killed  rabbits,  but  the 
poison  was  not  destroyed  by  boiling  and,  therefore,  could  not  have 
been  a  toxin.  Moreover,  the  poison  from  egg  white  is  quite  as  potent 
as  this.  The  poison  in  the  streptococcus  is  that  common  to  all  proteins 
and  it  is  probable  that  when  it  is  isolated  the  yield  from  the  protein 
substance  of  this  organism  will  be  less  than  the  average  from  proteins 
in  general.  In  other  words,  the  streptococcus  is  probably  not  rich  in 
poison.  If  it  were  otherwise,  recoveries  from  streptococcic  infection 
would  be  less  rare  than  they  are.  It  is  true  that  immune  sera  have 
been  prepared,  their  protective  value  demonstrated  on  animals  and 
their  beneficial  effects  in  man  shown,  but  they  do  not  act  like  anti- 
toxins. They  do  not  fulfil  the  law  of  multiple  proportions.  Their 
beneficial  effects,  so  far  as  they  have  any,  are  due  to  favoring  phago- 
cytosis and  not  to  neutralizing  a  toxin.  The  immune  sera  are 
obtained  by  treating  animals  with  strains  the  virulence  of  which  has 
been  greatly  increased  by  passage  through  animals,  and  while  certain 
amounts  of  the  serum  are  protective  against  certain  doses  of  the 
culture,  when  the  latter  remains  small,  multiple  amounts  of  the  serum 
fail  to  protect  against  like  amounts  of  the  culture.  Much  credit  is  due 
Marmorek,  Tavel,  Aronson,  Menzer  and  others  for  the  most  careful 
and  scientific  work  in  attempts  to  prepare  curative  sera  against 
streptococcic  infection.  Success  in  this  would  bring  to  medicine  a 
great  triumph  and  to  humanity  a  greater  blessing,  but  it  must  be 
admitted  that,  up  to  the  present  time,  the  problem  remains  without 
practical  solution,  and  prevention  rather  than  cure  must  demand  our 
best  efforts. 


CHAPTER    XXI 


STAPHYLOCOCCIC    INFECTION 

The  Organism. — In  his  study  of  wound  infection,  Ogston  recog- 
nized two  groups  of  bacteria  with  different  morphologic  characteristics. 
In  one  the  cocci  are  arranged  in  chains,  in  the  other  they  are  in  bunches. 
The  former  he  designated  as  streptococci  and  the  latter  as  staphylo- 
cocci.  Of  the  staphylococci  one  group  is  chromogenic  and  the  other 
is  not.  The  former  is  known  as  Staphylo coccus  pyogenes  aureus,  and 
the  latter  as  albus.  The  staphylococci  constitute  a  large  group  with 
many  varieties,  differing  more  or  less  widely  in  cultural,  tinctorial  and 
pathogenic  properties. 

The  individual  cocci  are  quite  variable  in  size,  which  seems  to  be 
influenced  by  food,  age  and  temperature.  They  take  the  basic  anilin 
stains  easily,  also  certain  acid  stains,  and  are  slightly  colored  by  hemo- 
toxylin.  The  readiness  with  which  such  a  variety  of  stains  may  be 
employed  has  favored  attempts  to  ascertain  the  finer  structures  of 
these  organisms.  Some  are  convinced  that  the  cocci  consist  of  a  distinct 
membrane  with  protoplasmic  content,  while  others  find  evidence  of 
well-defined  nuclei.  However,  all  of  this  work  needs  more  extended 
study  before  the  conclusions  reached  by  different  observers  can  be 
correlated  and  accepted. 

The  optimum  growth  temperature  is  that  of  the  animal  body, 
though  multiplication  continues  at  temperatures  as  high  as  43  C.  and 
as  low  as  10  C.  Free  oxygen  is  not  essential  and  growth  will  proceed 
in  proper  media  in  an  atmosphere  of  hydrogen,  but  not  in  carbonic 
acid,  nitrogen  or  illuminating  gas.  It  does  not  grow  abundantly  in 
media  containing  no  protein,  but  it  may  obtain  its  nitrogen  from 
ammonia  salts,  kreatin  or  asparagin.  It  develops  abundantly  in  pep- 
tone solutions,  but  this  is  not  an  essential  constituent  of  nutritive 
media.  A  feebly  alkaline  reaction  is  most  favorable,  but  feeble 
acid  does  not  prevent  growth.  In  bouillon  at  incubator  temperature 
multiplication  proceeds  with  great  rapidity ;  one  loop  of  such  a  culture 


162          .  STAPHYLOCOCCIC    INFECTION 

twenty-four  hours  old  may  contain  millions  of  living  cocci.  In  milk 
there  is  a  slow  evolution  of  acid  and  coagulation  results  after  about 
one  week.  It  slowly  liquefies  gelatin  by  the  formation  of  a  peptonizing 
ferment  This  ferment  converts  proteins  into  albumoses,  peptones, 
amins  and  ammonia. 

A  temperature  of  70  C.  (158  F.)  continued  for  five  minutes  suffices 
to  destroy  the  organism,  and  immediate  sterilization  is  secured  by 
boiling.  The  staphylococcus  is  highly  resistant  to  drying.  Dried  pus 
may  contain  viable  organisms  after  many  months  and  dust  may  harbor 
them  and  aid  in  their  distribution.  Mercuric  chlorid  in  dilution  as 
great  as  1 :  10,000  may  inhibit  growth  but  does  not  kill  these  bacteria. 
Indeed,  they  are  rather  resistant  to  this  germicide,  1 :  1,000  requiring 
several  hours  and  even  1 :  100  needing  from  five  to  ten  minutes. 
Absolute  alcohol  is  without  effect  but  50  per  cent,  alcohol  is  quite 
efficient  in  ten  minutes.  Phenol,  from  3  to  5  per  cent.,  kills  within 
five  minutes.  For  disinfecting  the  hands  lysol  followed  by  dilute  alco- 
hol is  recommended. 

The  staphylococcus  is  usually  found  on  the  skin,  the  albus  most 
frequently,  but  the  aureus  not  seldom.  It  is  also  present  in  normal 
saliva,  on  the  tonsils  and  walls  of  the  pharynx  and  in  the  conjunctival 
sac.  It  is  frequently  present  in  the  normal  urethra,  both  male  and 
female,  but  rarely  in  the  vagina.  It  collects  on  the  clothing  and  makes 
this  a  source  of  infection  when  carried  into  wounds.  It  is  often  found 
on  cold  foods  and  is  a  frequent  constituent  of  market  milk.  The 
strains  showing  this  wide  distribution  are  generally  of  low  virulence. 

Old  filtered  bouillon  cultures  of  the  staphylococcus  have  certain 
well-marked  effects.  They  contain  a  substance  which  induces  degen- 
erative and  destructive  changes  in  leukocytes  and  for  this  reason  is 
known  as  leukocidin.  This  substance  has  not  been  isolated  and  its 
presence  is  indicated  by  its  effects.  It  is  inactivated  at  60  and  is  sup- 
posed to  be  a  ferment.  When  leukocytes  are  subjected  to  filtered 
cultures  of  the  staphylococcus,  they  soon  show  degenerative  changes 
and  finally  lose  their  nuclei.  Leukocytes  from  different  animals  vary 
greatly  in  susceptibility  to  this  agent.  Those  from  the  frog  are 
undisturbed ;  from  the  mice  and  guinea-pigs,  slightly  susceptible ;  from 
the  dog,  more,  and  from  the  rabbit,  most  susceptible. 


STAPHYLOCOCCIC    INFECTION  163 

The  old  filtered  cultures  agglomerate  and  dissolve  red  blood  cells. 
Only  in  dilute  or  weak  solutions  is  agglutination  observable;  in  strong 
solutions  there  is  rapid  or  immediate  hemolysis.  The  hemolytic  agent 
is  most  in  evidence  in  cultures  from  six  to  ten  days  old.  However, 
this  is  variable  and  it  may  be  more  abundant  in  still  older  cultures. 
Whether  it  is  the  same  agent  that  acts  on  the  white  and  red  corpuscles 
is  not  certainly  known,  but  both  effects  are  prevented  by  heating  the 
filtrate  to  60  C. 

Both  antileukocidin  and  antihemolysin  are  easily  prepared  by 
repeated  injections  of  small  doses  of  filtered  cultures  of  the  staphylo- 
coccus  in  animals.  This  is  further  evidence  that  these  bodies  are 
toxins  and  should  be  classed  among  the  ferments. 

Filtered  cultures  when  injected  into  animals  have  injurious  effects 
on  other  cells.  Hyalin  casts  are  formed  in  the  uriniferous  tubules 
and  necrotic  areas  appear  in  the  kidney  cortex.  The  subcutaneous 
tissue  about  the  point  of  injection  becomes  indurated,  the  hairs  over 
it  fall  out  and  in  some  instances  necrosis  results.  Some  investigators 
have  observed  similar  changes  in  the  intestinal  mucosa  and  others 
report  degenerative  changes  in  the  central  nervous  system.  It  will 
appear  from  these  statements  that  the  staphylococcus,  living  or  dead,  is 
harmful  to  body  cells.  Whether  the  noxious  constituents  of  filtered 
cultures  are  to  be  considered  as  secretions  of  the  cocci  or  as  frag- 
ments resulting  from  autolytic  cleavage  has  not  been  definitely  deter- 
mined, though  the  prevalent  opinion  is  in  favor  of  the  first  alternative. 

It  has  long  been  known  that  amyloid  degeneration  results  in  man 
after  long-continued  suppurative  processes.  This  change  has  been 
induced  in  animals  by  repeated  small  inoculations  of  living  cultures 
and  by  injection  of  dead  cultures. 

Bail  and  his  students  have  used  the  staphylococcus,  as  well  as 
other  bacteria,  in  the  study  of  their  aggressins.  A  large  amount  of 
an  agar  culture  of  a  staphylococcus,  whose  virulence  has  been  greatly 
increased  by  passage  through  animals,  is  injected  into  the  pleural 
cavity  of  a  rabbit.  The  exudate  which  is  formed  is  drawn  off  and 
found  to  contain  cocci,  dissolved  red  corpuscles  and  degenerated 
leukocytes.  This  is  freed  from  bacteria  by  centrifugation  and  then 
it  is  found  that  some  of  the  supernatant  fluid  plus  less  than  a  fatal 
dose  of  the  staphylococcus  injected  into  a  half-grown  rabbit,  kills  it 


164  STAPHYLOCOCCIC    INFECTION 

in  a  few  hours.  After  death  the  pleural  exudate  in  this  animal  is 
found  to  be  sterile.  Therefore,  the  animal  does  not  die  from  infection 
but  from  intoxication.  Bail's  explanation  is  that  the  exudate  is  bac- 
tericidal and  in  the  second  animal  quickly  splits  up  the  cocci  with  the 
liberation  of  enough  poison  to  kill  it.  This  seems  not  only  rational, 
but  the  most  probable  explanation. 

In  most  of  the  suppttrative  affections  of  man  either  the  strepto- 
coccus or  the  staphylococcus,  or  both,  play  some  part,  either  as  primary 
or  secondary  cause.  Other  bacteria  may  be  present,  but  these  are  the 
most  essential.  It  is  true  that  there  may  be  an  aseptic  suppuration 
and  it  is  also  true  that  other  bacteria  may  incite  suppurative  processes, 
but  these  are  rare  exceptions.  Among  the  cutaneous  and  subcutaneous 
lesions  which  may  be  due,  either  wholly  or  in  part,  to  the  staphylo- 
coccus, we  may  mention  acne,  erysipelas,  impetigo,  lymphangitis,  boils, 
abscesses,  phlegmons  and  pemphigus.  In  the  alimentary  canal  this 
organism  may  infect  any  part  from  the  beginning  to  the  end.  Rarely 
it  closely  simulates  diphtheria  in  the  formation  of  membrane,  and  the 
osseous  system  seems  to  furnish  favorable  conditions  for  its  growth. 
Abscesses  in  various  parts  of  the  body  are  most  frequently  due  to  this 
organism  alone  or  in  company  with  the  streptococcus.  Among  our 
domestic  animals  it  causes  the  same  or  similar  lesions. 

While  it  is  true  that  the  serum  of  an  animal  highly  immunized  to 
the  staphylococcus  agglutinates  this  organism  in  fairly  high  dilutions, 
serodiagnosis  of  staphylococcic  infection  has  not  proved  of  great  value. 
Fortunately,  it  is  rarely  needed. 

The  contest  between  the  phagocytes  and  the  pus  germs  is  waged  on 
fairly  even  terms.  Each  secretes  an  agent  which  is  destructive  to  the 
other.  The  cocci  prepare  and  use  the  leukocidin,  and  the  phagocytes 
employ  a  bactericidal  ferment.  The  contestants  are  wary  in  approach 
and  frequently  retreat.  When  the  cocci  are  only  slightly  virulent 
and  form  but  little  or  no  leukocidin,  the  phagocytes  are  bold  and 
rapidly  devour  their  enemies.  In  this  case,  we  say  that  the  chemotaxis 
is  positive.  But  when  the  cocci  are  highly  virulent  and  pour  out  large 
amounts  of  leukocidin,  the  phagocytes  approach  with  greater  caution 
or  retreat.  Then,  we  say  that  the  chemotaxis  is  negative.  Phagocytes 
feed  voraciously  on  unarmed  cocci,  but  when  the  latter  are  prepared, 
the  former  seem  less  hungry.  The  leukocidin  is  best  prepared  for  study 


STAPHYLOCOCCIC    INFECTION  165 

by  filtering  old  highly  virulent  cultures  of  the  cocci,  while  the  coccidal 
agent  is  obtained  by  forming  pleural  exudates  and  separating  the 
remaining  cocci  by  centrifugation.  Evidently  the  phagocytes  may  be 
strengthened  in  this  contest  in  two  ways.  First,  anything  which  will 
improve  their  effectiveness  will  improve  their  chances,  and  second, 
anything  which  will  lessen  the  leukocidin  of  the  cocci  or  render  it  inert, 
will  help  the  phagocytes.  Vaccination  as  introduced  by  Wright  is  an 
attempt  to  help  the  phagocytes  in  this  contest.  Within  a  limited  field, 
Wright's  method  of  treating  disease  by  vaccination  has  proved  suc- 
cessful. The  best  results  have  been  secured  in  the  treatment  of  such 
pustular  diseases  as  acne  and  furunculosis.  In  these  diseases  the  cocci 
are  as  it  were  entrenched  and  the  phagocytes  are  slow  to  attack.  By 
injecting  cocci  into  the  midst  of  the  leukocytes  the  latter  are  stimu- 
lated through  devouring  easily  the  prey  thus  thrown  to  them.  The 
formation  of  bactericidal  ferments  by  the  phagocytes  is  improved  by 
exercise  and  this  advantage  brings  victory  to  them.  In  the  vaccine 
treatment  of  disease  there  is  always  danger  of  overdoing  the  stimula- 
tion of  the  leukocytes.  It  has  worked  better  with  pus  bacteria  than 
with  others,  probably  for  the  reason  that  the  cocci  protein  is  not  rich 
in  poison. 


CHAPTER    XXII 


DIPHTHERIA 

History. — Under  various  names  this  disease  is  described  in  the 
most  ancient  medical  records.  Competent  authority  states  that  a 
disease  mentioned  in  the  Babylonian  Talmud  must  have  been  diph- 
theria. The  Greeks  held  that  it  came  to  them  from  Egypt,  to  which 
country  they  were  wont  to  ascribe  most  of  their  ills.  The  descriptions 
of  Aretaeus  are  regarded  as  accurate  records  of  this  disease.  Galen 
spoke  of  false  membranes  in  the  larynx  and  pharynx  and  said  that  the 
former  were  sometimes  removed  by  coughing,  and  the  latter  by  hawk- 
ing. During  the  dark  ages  diphtheria  was  recognized  here  and  there 
and  undoubtedly  added  much  to  the  high  death-rate  of  that  period. 
During  the  sixteenth  century  it  was  reported  from  time  to  time  in 
malignant  epidemic  form  in  Spain,  France,  Holland  and  Germany. 
The  unusual  mortality  in  Spain  in  1613  gave  to  this  year  the  name  of 
the  disease.  In  the  same  country  and  in  the  same  century,  Heredia 
recognized  the  asthenic  and  suffocative  types  and  wrote  concerning 
diphtheria  paralysis.  Before  the  middle  of  the  seventeenth  century 
it  had  found  its  way  into  the  American  colonies  and  we  are  told  that  in 
the  year  1659  Samuel  Danforth  lost  four  of  his  eleven  children  of  "a 
malady  of  the  bladders  in  the  windpipe."  As  early  as  1761,  an  Ameri- 
can physician,  Bard,  made  important  contributions  to  the  study  of  the 
disease  and  held  that  croup  is  laryngeal  diphtheria.  However,  we  owe 
the  beginnings  of  the  modern  study  of  this  disease,  also  its  present 
name,  to  Bretonneau.  He  traced  an  outbreak  in  a  garrison  at  Tours 
to  common  drinking-cups  and  other  table  utensils,  and  demonstrated 
the  infectiousness  of  the  disease.  He  claimed  that  croup  is  laryngeal 
diphtheria  and  that  the  angina  of  scarlet  fever  is  quite  distinct.  These 
views  were  accepted  and  emphasized  by  the  great  clinician,  Trousseau, 
and  were  adopted  by  the  profession  in  France  and  America,  but  were 
ignored  in  Germany  until  the  development  of  bacteriology  rendered 
their  demonstration  possible. 


168  DIPHTHERIA 

During  the  sixties  of  the  past  century,  many  were  busy  searching 
for  the  particulate  cause  of  this  disease  and  several  organisms  were 
presented  as  claimants  for  this  honor,  but  at  that  time  bacteriologic 
methods  had  not  been  sufficiently  developed  to  enable  the  most  expert 
to  pick  out  the  one  responsible  for  the  disease.  In  1883  Klebs  called 
attention  to  a  bacillus  with  well-marked  characteristics,  frequently 
found  in  diphtheritic  throats,  and  a  year  later  Loffler  continued  this 
work. 

The  Bacillus.  —  The  Klebs-Loffler  bacillus  is  a  non-motile  rod, 
generally  straight,  but  sometimes  slightly  bent.  Its  length  is  quite 
variable  (from  3  to  5  microns)  and  its  breadth  almost  one-fourth  its 
length.  The  most  characteristic  form  of  the  bacillus  is  the  club  shape. 
All  the  rods  do  not  have  this  form,  but  in  every  field  there  are  many 
so  characteristically  clubbed  that  the  expert  has  no  difficulty  in  identi- 
fication at  sight.  This  is  true  especially  of  cultures  made  directly 
from  the  throat.  Even  the  presence  of  other  bacteria  does  not  prevent 
identification.  A  sterilized  cotton  swab  is  drawn  over  the  membrane 
in  the  throat  and  then  over  the  surface  of  a  slant  serum  tube.  After 
from  six  to  twelve  hours  in  the  incubator,  a  stain  is  made  from  the 
growth  on  the  serum.  While  the  diphtheria  bacillus  takes  most  basic 
stains  well,  Loffler's  alkaline  methylene  blue  is  most  generally  employed. 
Direct  microscopic  examination  of  this  stain  enables  the  expert  to 
determine  with  certainty  in  the  great  majority  of  instances  the  presence 
or  absence  of  the  specific  organism  and  announce  the  bacteriologic 
diagnosis.  The  bacteriologist  does  not  depend  solely  on  the  presence 
of  club-shaped  bacilli.  The  Klebs-LorHer  bacillus  has  a  peculiar  seg- 
mented appearance  when  colored  with  the  stain  mentioned  above. 
This  is  more  easily  recognized  than  described,  but  it  becomes  so 
familiar  to  one  engaged  in  this  work  that  he  is  seldom  mistaken.  The 
morphologic  identification  is  rendered  more  easy  by  the  fact  that  as  a 
rule  the  only  other  bacteria  on  the  slide  are  streptococci.  If  the  observer 
satisfies  himself  that  only  streptococci  are  present,  he  makes  a  negative 
report.  In  a  few  instances,  there  are  diphtheria-like  organisms  which 
may  leave  one  in  doubt.  However,  when  in  doubt  the  only  wise  thing 
to  do  is  to  make  a  positive  diagnosis,  when  the  case  will  be  properly 
isolated  and  treated  with  antitoxin. 


DIPHTHERIA  169 

Subcultures  of  the  diphtheria  bacillus  show  many  and  varied  invo- 
lution forms.  Many  attempts  have  been  made  to  establish  a  relation- 
ship between  morphology  and  virulence,  but  these  have  led  to  no 
practical  results.  The  Loffler  serum  should  be  carefully  prepared  and 
should  consist  of  three  parts  of  serum  (horse,  ox  or  sheep)  and  one 
part  of  neutral  bouillon  containing  1  per  cent,  each  of  peptone  and 
grape  sugar.  The  freshly  prepared  serum  should  be  shaken  for  some 
hours  with  3  per  cent,  chloroform  before  the  bouillon  is  added.  On 
one  day  the  serum  is  heated  for  from  five  to  six  hours  at  from  70 
to  80  C.  (158  to  176  R).  On  the  next  day  it  should  be  held  at  80  C. 
for  one  hour  and  for  the  same  time  at  90  (194  F.),  and  then  for  half 
this  time  at  100  C.  (212  F.),  and  then  allowed  to  harden  slowly.  On 
this  medium  the  bacillus  will  form  a  good  growth  in  the  incubator 
within  six  hours. 

The  optimum  growth  temperature  is  about  37  C.,  but  growth  pro- 
ceeds anywhere  between  20  and  41  C.  While  air  is  not  absolutely  essen- 
tial, growth  is  most  rapid  when  this  is  abundantly  supplied.  In  liquid 
cultures,  a  scum  forms  on  top,  and  the  subjacent  fluid  may  remain 
clear.  The  sides  of  the  tube  may  be  covered  with  the  growth.  On 
ordinary  agar  the  development  is  slow  and  scanty.  Gelatin  colonies 
are  not  characteristic  and  the  medium  is  not  liquefied.  In  the  presence 
of  certain  carbohydrates  there  is  a  slow  production  of  acid,  but  this 
does  not  occur  in  bouillon  when  the  muscle  sugar  has  been  removed. 
In  the  absence  of  carbohydrates  from  the  medium,  the  alkalinity  is 
increased. 

The  resistance  of  this  bacillus  to  untoward  conditions  depends  on 
whether  it  is  still  protected  by  its  membrane  or  has  been  freed  from 
the  same.  The  membrane,  even  when  partially  dried,  may  retain 
its  virulence  for  many  months.  On  the  other  hand,  silk  threads  dipped 
in  cultures  and  exposed  to  direct  sunlight  soon  become  inert.  Phenol, 
5  per  cent,  and  mercury  chlorid,  1 :  1,000,  destroy  the  bacillus  within 
five  minutes.  Absolute  alcohol  has  but  little  or  no  effect,  but  when  the 
strength  is  reduced  to  from  60  to  30  per  cent,  a  few  minutes  suffice  to 
kill  the  bacilli.  According  to  Meyer,  certain  tooth  pastes  destroy  diph- 
theria bacilli  in  less  than  one  minute.  It  must  not  be  inferred  from 
this  that  a  diphtheritic  mouth  could  be  easily  disinfected  by  such  an 
agent.  The  bacilli  are  protected  by  the  pharyngeal  folds  and  the  crypts 


170  DIPHTHERIA 

of  the  tonsils.  However,  since  the  healthy  carrier  plays  a  large  part 
in  the  distribution  of  this  disease,  more  attention  to  oral  hygiene  might 
be  of  service  in  this  as  well  as  other  directions. 

Roux  and  Yersin  discovered  diphtheria  toxin.  Cultures  several 
weeks  old  were  filtered  through  porcelain.  The  germ-free  filtrate  in 
minute  doses  kills  animals.  The  toxin  has  not  been  obtained  in  a 
pure  state,  and  we  are  still  in  doubt  concerning  its  chemical  composi- 
tion. It  resembles  in  some  respects  the  ferments.  It  acts  slowly 
and  after  a  period  of  incubation;  it  is  active  in  exceedingly  small 
amounts;  it  is  destroyed  by  heat,  and  when  repeatedly  injected  into 
animals  in  non- fatal,  but  increasing,  doses,  the  animal  becomes  immune 
by  elaborating  an  antibody.  In  these  respects  diphtheria  toxin 
resembles  the  ferments.  It  differs  from  many  ferments  in  the  fact 
that  a  given  amount  produces  only  a  certain  effect  and  apparently 
goes  no  further.  Different  strains  of  the  bacillus  show  wide  variations 
in  their  toxin  production,  and  the  highest  toxin  producers  are  not 
always  the  most  virulent  bacilli.  What  is  called  diphtheria  toxin  is  an 
old  filtered  culture,  and  the  strength  of  this  is  determined  by  ascertain- 
ing the  minimum  amount  necessary  to  kill  a  guinea-pig  of  from  200  to 
250  gm.  weight  within  four  days.  This  minimum  lethal  dose  may 
be  as  small  as  0.0005  c.c.,  though  that  usually  employed  in  the  pro- 
duction of  antitoxin  is  much  less  powerful  than  this. 

The  effect  of  this  toxin  on  animals  has  opened  a  new  field  of 
research,  has  given  a  new  understanding  of  disease  processes  and  has 
led  to  one  of  the  most  beneficent  discoveries,  that  of  diphtheria  anti- 
toxin. When  a  fatal  dose  of  this  toxin  is  injected  into  an  animal, 
there  is  a  period  of  incubation  during  which  the  animal  shows  no 
marked  departure  from  the  normal.  This  incubation  period  varies 
with  the  size  of  the  dose,  but  is  never  less  than  about  eight  hours,  even 
when  many  times  the  fatal  amount  has  been  used.  The  significance 
of  this  incubation  has,  in  the  writer's  opinion,  been  misunderstood.  It 
should  not  be  inferred  that  nothing  happens  during  this  time.  The 
disturbance  simply  does  not  rise  to  the  plane  of  gross  clinical  observa- 
tion. The  toxin  begins  to  act  soon  after  its  introduction.  Within  an 
hour  or  two  the  temperature  begins  to  rise  and  proceeds  slowly  until 
some  hours  before  death  when  it  begins  to  fall,  and  at  death  it  is 
several  degrees  below  normal.  The  skin  about  the  point  of  injection 


DIPHTHERIA  171 

becomes  edematous  and  later  necrotic.  The  interval  between  injection 
and  death  is  the  same  as  after  inoculation.  With  sublethal  doses  there 
is  often  paralysis,  beginning  in  the  posterior  extremities  and  extending 
over  the  body.  The  internal  organs  are  hyperemic  with  hemorrhages 
in  the  adrenals,  stomach  and  intestine.  Sometimes  a  gastric  ulcer  is 
found.  It  is  important  to  note  that  after  the  first  day  there  is  a  fall 
in  the  blood  pressure.  The  effects  of  the  toxin  on  temperature  and 
blood  pressure  suggest  the  action  of  the  protein  poison.  It  will  prob- 
ably be  found  that  the  toxin  is  a  ferment  which  slowly  disrupts  some 
protein,  setting  free  the  poison  which  in  small  amount  increases  and 
in  larger,  decreases  the  temperature  and  lowers  blood  pressure.  The 
toxin  apparently  has  special  avidity  for  nervous  tissue.  Whether  this 
action  is  primarily  central  or  peripheral  has  not  been  determined. 
When  the  toxin  is  injected  into  a  susceptible  animal  it  soon  disappears 
from  the  blood  current  and  manifests  its  activity  on  certain  organs 
and  tissues.  It  has  not  been  found  in  the  urine  except  when  massive 
doses  are  given.  In  insusceptible  animals,  it  remains  for  a  long  time 
in  the  blood  stream  and  is,  of  course,  without  action  on  the  tissues. 
It  is  not  able  to  digest  the  animal's  proteins  and  it  is  for  this  reason 
that  the  animal  is  refractory. 

We  owe  the  discovery  of  diphtheria  antitoxin,  one  of  the  most 
beneficent  discoveries  of  all  ages,  to  the  labors  and  genius  of  von 
Behring.  It  is  true  that  others  had  prepared  the  way,  but  this  detracts 
in  no  way  from  the  debt  of  gratitude  the  world  owes  this  distinguished 
German  investigator.  To  the  preliminary  work  America  made  two 
important  contributions.  Mitchell  and  Reichert  showed  that  the  active 
principles  in  the  venom  of  serpents  are  protein  bodies  or  so  closely 
related  to  proteins  that  they  have  not  been  separated.  Sewall  immu- 
nized pigeons  to  this  venom.  Then  came  the  discovery  by  the  French- 
men, Roux  and  Yersin,  of  diphtheria  toxin,  closely  resembling  snake 
venom  in  its  action.  Ehrlich  immunized  animals  to  the  similar 
vegetable  poisons,  abrin,  ricin  and  robin,  and  demonstrated  that  passive 
immunity  could  be  established  in  other  animals  by  the  transference  to 
them  of  the  serum  of  those  actively  immunized.  Von  Behring's  method 
of  preparing  diphtheria  antitoxin  as  now  used  is  as  follows:  Sound, 
healthy  horses  are  kept  under  observation  and  tested  with  mallein  to 
insure  freedom  from  glanders.  Injections  of  diphtheria  toxin,  begin- 


172  DIPHTHERIA 

ning  with  very  small  doses,  are  given  these  animals  at  intervals  of 
a  few  days.  It  is  desirable  that  the  first  doses  should  be  so  small  that 
marked  local  or  general  reactions  are  not  induced.  Horses  differ 
widely  in  susceptibility  to  the  toxin.  From  time  to  time  a  small  amount 
of  blood  is  drawn  from  the  horse  and  its  protective  power  against  the 
toxin  is  tested  on  guinea-pigs.  The  amount  of  the  serum  necessary 
to  protect  a  guinea-pig  of  250  gm.  weight  against  100  minimum  lethal 
doses  of  the  toxin  is  known  as  an  "immunity  unit."  When  the  pro- 
tective value  of  the  serum  has  risen  to  the  desired  point,  from  4  to  8 
liters  of  blood  are  drawn  under  aseptic  precautions  into  sterilized  glass 
cylinders.  These  are  allowed  to  stand  in  a  cool,  dark  place  until 
coagulation  is  complete,  when  the  serum  is  treated  with  some  preserva- 
tive, such  as  0.5  per  cent,  phenol,  0.4  per  cent,  trikresol  or  a  small 
amount  of  camphor,  and  placed  in  containers  ready  to  be  injected  into 
the  sick  person.  In  some  countries  no  preservative  is  used  and  the 
serum  is  heated  to  56  C.  In  all  countries  antitoxin  is  made  under 
governmental  supervision  and  the  product  is  tested  in  some  laboratory. 
All  horses  do  not  produce  the  same  grade  of  antitoxin,  and  sera 
from  different  animals  are  mixed  and  the  product  tested  as  to  its 
protective  value.  Some  horses  continue  to  produce  a  high  grade  anti- 
toxin for  years  and  from  4  to  6  liters  of  serum  may  be  obtained  from 
such  animals  monthly.  It  will  be  understood  that  in  such  cases  the 
injections  of  toxin  must  be  regularly  repeated.  Immediately  after  an 
injection  of  toxin  the  antitoxin  content  of  the  blood  falls,  then  it  rises 
and  generally  reaches  its  highest  point  in  ten  or  twelve  days,  remaining 
at  that  point  for  a  variable  time.  The  horse  has  been  immunized  by 
the  repeated  injections  of  the  toxin.  The  process  of  immunization 
consists  in  developing  in  the  animal's  body  an  antitoxin,  the  excess  of 
which  is  in  the  blood,  and  in  the  serum  after  coagulation.  The  anti- 
toxin is  capable  of  neutralizing  the  toxin  both  in  vitro  and  in  vivo. 
The  diphtheria  bacillus  is  growing  in  the  throat  of  the  child  and  pour- 
ing its  toxin  into  the  child's  blood.  The  blood  serum  of  the  horse 
is  injected  into  the  child  and  neutralizes  the  toxin  coming  from  the 
throat.  The  horse  has  been  immunized,  and  when  its  blood  serum  is 
introduced  into  the  child,  the  child  becomes  for  the  time  physiologically 
a  part  of  the  horse  and  partakes  of  the  horse's  immunity  just  to  the 
extent  of  the  amount  and  potency  of  the  horse's  serum  injected.  It 


DIPHTHERIA  173 

should  be  understood  that  the  blood  serum  of  the  horse  containing 
the  antitoxin  is  not  bactericidal.  It  does  not  kill  the  bacilli  in  the 
throat,  but  it  neutralizes  the  toxin  in  the  blood  and  tissues.  It  must 
be  evident  from  this  that  the  earlier  in  the  disease  the  antitoxin  is 
used,  the  more  beneficial  it  is.  When  the  toxin  poured  from  the  throat 
into  the  blood  meets  with  no  antibody,  it  acts  on  the  body  cells  and 
destroys  them,  and  to  the  extent  to  which  this  has  been  done  before 
the  antitoxin  has  been  administered,  it  is  without  value.  Kossel  has 
shown  that  when  the  antitoxin  is  injected  on  the  first  sign  of  the 
disease,  the  percentage  of  recoveries  is  100.  In  this  every  hour  counts. 
Out  of  2,428  cases  reported  by  Hilbert,  the  percentage  of  deaths 
varied  with  the  day  on  which  the  antitoxin  was  administred,  as  follows : 
First  day,  2.2;  second  day,  7.6;  third  day,  17.1 ;  fourth  day,  23.8;  fifth 
day,  33.9;  sixth  day,  34.1;  after  the  sixth  day,  38.2.  According  to 
Wernicke  the  saving  of  lives  during  the  first  year  of  the  use  of  anti- 
toxin in  Germany  amounted  to  20,000,  and  if  the  agent  was  properly 
and  promptly  used  the  saving  would  amount  to  45,000  lives  annually. 
The  value  of  this  agent,  however,  is  even  greater  than  is  indicated  by 
the  lowering  in  the  death-rate.  For  every  sick  child  saved,  at  least 
five  are  saved  from  being  sick.  While  the  curative  value  of  diphtheria 
antitoxin  is  great,  its  preventive  value  is  greater  still.  The  physician 
called  to  a  family  in  which  one  child  has  diphtheria  gives  a  curative 
dose  to  the  one  and  immunizing  doses  to  all  others.  Even  when  the 
sick  one  has  been  neglected  so  long  that  the  curative  value  of  the  agent 
is  lost,  its  preventive  value  is  still  potent.  Diphtheria  antitoxin  has 
lowered  not  only  the  mortality  rate,  but  still  more  the  morbidity  rate. 
Unfortunately,  the  immunity  induced  by  diphtheria  antitoxin  is  only 
temporary,  lasting  only  from  three  to  four  weeks.  From  this  it 
frequently  happens  that  a  child. who  has  once  had  an  immunizing  dose, 
may  a  few  months  or  possibly  a  few  years  later,  need  a  curative  dose. 
The  fear  of  anaphylactic  shock  has  led  many  a  physician  to  hesitate 
about  a  "reinjection"  of  horse  serum  after  an  interval  of  ten  days  or 
longer,  but  one  may  do  this  with  safety.  In  all  cases  of  "reinjection" 
after  an  interval  of  ten  days  or  longer,  a  fraction  of  a  cubic  centimeter 
should  be  injected.  If  there  are  or  are  not  untoward  symptoms  follow- 
ing this,  after  an  hour  or  two  any  amount  of  the  serum  may  be  injected 
with  safety.  This  procedure  should  be  adopted  not  only  in  all  cases 


174  DIPHTHERIA 

of  rein j action,  but  when  the  patient  has  ever  shown  asthmatic 
symptoms.  With  these  precautions  no  physician  need  fear  to  use 
diphtheria  antitoxin  when  it  is  needed.  In  order  to  prevent  outbreaks, 
Heubner,  for  the  past  twenty  years,  has  had  every  child  in  his  hospital 
injected  every  fourteen  days  and  no  serious  result  has  ever  followed. 

When  antitoxin  is  used  early  in  the  disease,  the  extension  of  the 
membrane  usually  stops  in  a  few  hours.  For  this  reason,  laryngeal 
diphtheria  is  now  rarely  seen  except  in  neglected  cases.  Not  only  does 
the  extension  of  the  membrane  stop  on  the  administration  of  the  anti- 
toxin, but  as  a  rule  that  already  formed  begins  to  recede,  becomes 
detached  and  fades  away.  It  may  truly  be  said  that  the  discovery  of 
antitoxin  has  largely  robbed  diphtheria  of  its  terrors,  and  it  might 
not  be  amiss  to  call  attention  to  the  fact  that  without  animal  experi- 
mentation this  could  not  have  been  done.  Hundreds  of  animals  have 
been  sacrificed  in  order  that  hundreds  of  thousands  of  human  lives 
might  be  saved  from  one  of  the  most  distressing  forms  of  death  man 
has  known. 

Notwithstanding  the  possession  of  this  wonderful  and  almost  mir- 
aculous preventative  and  curative  agent,  the  problem  of  the  eradica- 
tion of  diphtheria  remains  one  of  the  most  difficult  problems  still  con- 
fronting scientific  medicine.  The  bacillus  seems  well-nigh  ubiquitous. 
Thousands  of  people  in  health  carry  these  deadly  germs  in  their  throats 
and  mouths.  If  it  has  breeding  places  outside  the  human  body  they 
have  not  been  discovered.  The  disease  is  acquired  for  the  most  part 
at  least,  not  from  those  ill,  but  from  those  who  are  in  apparent  health. 
All  that  we  can  do  at  present  is  to  emphasize  the  desirability  of  more 
individuality  and  less  promiscuity  in  manners  of  life.  The  common 
drinking-cup  and  other  methods  of  contact  with  lip  to  lip  directly  and 
indirectly  must  be  discouraged  and  the  importance  of  oral  hygiene 
must  be  emphasized,  especially  among  children. 


PART   II 

IMMUNITY 


CHAPTER    XXIII 


INTRODUCTION 

Had  the  animal  body  no  effective  means  of  resistance  to  bacterial 
invasion,  man  could  not  have  developed,  and  the  whole  animal  world 
would  have  perished  long  since,  so  abundant  in  numbers  and  so  wide 
in  distribution  are  the  various  forms  of  bacterial  life,  both  saprophytic 
and  pathogenic.  In  life  our  skin  is  covered  with  bacteria  and  our 
alimentary  tract  filled  with  them.  Even  in  the  most  perfect  states  of 
health  we  are  the  hosts  and  they  are  our  guests.  Willingly  or  unwill- 
ingly, and  for  the  most  part  unconsciously,  we  supply  homes  and  food 
to  these  parasites.  With  the  approaching  death  of  the  host,  these 
myriads  begin  to  penetrate  every  part  of  our  bodies,  and  by  the  time 
the  respiration  and  pulse  cease,  both  saprophytes  and  parasites  are 
tearing  to  pieces  our  mortal  frames.  It  follows  from  this  that  the 
living  animal  must  possess  certain  agencies  which  serve  to  protect  it 
against  bacterial  invasion,  and  it  is  our  purpose  to  inquire  into  the 
nature  and  action  of  these  agencies. 

Different  species  of  animals  differ  widely  in  their  susceptibility  to 
a  given  pathogenic  bacterium.  As  a  rule  at  least,  it  is  true  that  the 
more  widely  separated  the  species  the  more  marked  is  the  difference 
in  susceptibility  to  the  same  infection.  We  know  of  no  bacterial  infec- 
tion common  to  the  cold  and  warm-blooded  animals.  It  is  true  that 
we  acquire  typhoid  fever  by  eating  oysters  taken  from  infected  water, 
but  the  oysters  do  not  have  typhoid  fever  any  more  than  the  leaves 
of  lettuce,  which  may  be  soiled  with  typhoid  excreta,  do.  Fish,  turtles 
and  possibly  other  cold-blooded  animals  have  tuberculosis,  but  this 
is  due  to  quite  a  different  organism  from  that  which  causes  this  dis- 
ease in  man.  Some  cold-blooded  animals  may  be  infected  experimen- 
tally with  anthrax  and  plague,  but  under  natural  conditions  they  are 
not  known  to  develop  these  diseases.  In  some  instances  at  least,  the 
immunity  of  cold-blooded  animals  to  bacteria  pathogenic  to  the  warm- 
blooded seems  to  be  solely  a  matter  of  temperature.  When  kept  at 


178  IMMUNITY 

warm-blood  temperature,  certain  cold-blooded  animals  become  sus- 
ceptible to  tetanus  and  other  infections.  Likewise,  warm-blooded  ani- 
mals are  immune  to  many  bacteria  because  they  cannot  grow  at  the 
temperature  of  the  animal  body.  This  is  true  of  the  greater  number 
of  the  saprophytic  bacteria  found  in  drinking-water.  A  bacterium 
which  cannot  grow  and  multiply  at  the  temperature  of  the  animal  body 
cannot  infect  the  animal.  Such  an  organism  may  produce  a  substance 
outside  the  body  and  at  its  growth  temperature,  which  is  poisonous 
to  a  warm-blooded  animal,  but  it  cannot  infect  the  animal. 

Like  differences  in  susceptibility  are  observed  in  birds  and  mam- 
mals. So  far  as  we  know,  under  natural  conditions,  there  is  no  trans- 
ference of  infection  between  these  classes.  With  larger  doses,  or 
under  unnatural  conditions  the  infection  of  mammals  may  be  trans- 
ferred to  birds.  Chickens  become  susceptible  to  some  of  these  infec- 
tions, such  as  anthrax,  when  the  body  temperature  is  kept  low.  Chick- 
ens have  tuberculosis,  but  the  bacillus  of  avian  tuberculosis  grows  at 
45  and  even  at  50  C.  while  that  of  the  human  does  not  grow  above 
41  C.  (105.8  F.).  While  barnyard  fowls  have  frequent  opportunity 
to  pick  up  the  sputum  of  tuberculous  men,  they  do  not  become  infected 
in  that  way,  nor  are  men  infected  with  avian  bacilli,  although  the 
opportunities  are  quite  frequent.  It  must  not  be  inferred  that  tem- 
perature is  the  only  factor  in  these  differences  in  susceptibility.  It 
seems  to  be  one  factor.  The  difference  in  metabolism  is  probably 
quite  as  great  a  factor,  possibly  much  greater,  but  its  value  is  not  so 
easily  determined.  Here  also,  the  poisons  produced  by  avian  infective 
bacteria  may  prove  harmful  to  mammals.  Man  may  eat  birds  dead 
of  chicken  cholera  and  by  doing  so  he  does  not  acquire  the  disease, 
but  he  may  be  more  or  less  severely  poisoned  by  the  bacterial  products. 

Between  herbivorous  and  carnivorous  animals  the  differences  are 
not  so  great.  The  latter  are,  as  a  rule,  much  less  susceptible  but  suc- 
cumb to  large  inoculations.  Anthrax,  one  of  the  most  universal  infec- 
tions, is  not  known  to  appear  in  epidemic  form  among  carnivorous 
animals  under  natural  conditions.  There  are  traditions  that  this  has 
happened,  but  these  are  not  based  on  reliable  information.  In  his 
susceptibility  to  infection  man  is  more  closely  related  to  the  herbivora 
than  to  the  carnivora.  Beasts  of  prey  may  become  infected  with 


IMMUNITY  179 

anthrax  or  glanders  when  fed  with  large  quantities  of  infected  material, 
but  this  is  not  comparable  with  natural  infection.  Smith  reports 
tuberculosis,  due  to  human  bacilli,  in  a  tame  bear  whose  master  had  the 
disease.  Possibly  with  closer  association  such  cases  would  be  more 
frequent.  Man  seems  to  possess  complete  immunity  to  rinderpest,  and 
apparently  none  of  our  domestic  animals  are  susceptible  to  scarlet 
fever  or  measles.  The  immunity  of  the  lower  animals  to  cholera  and 
typhoid  fever  may  be  due  to  their  normal  intestinal  bacteria. 

When  we  confine  our  attention  to  man,  variations  in  susceptibility 
among  the  races  is  not  so  great  as  was  once  believed.  Livingstone 
found  no  trace  of  syphilis  among  the  Africans  and  believed  these  people 
to  be  immune  to  this  infection,  but  as  early  as  1867,  Fritsch  reported 
it  rare  but  saw  occasional  cases  which  he  attributed  to  contact  with  the 
white  man.  More  recently,  this  disease  has  become  common  in  the 
Congo  and  coast  colonies,  and  in  Uganda  it  is  said  to  have  become  a 
veritable  plague.  Mense  states  that  the  bearers  of  culture  have  car- 
ried the  gifts  of  civilization  and  the  scourge  of  venereal  disease  to 
trustful  savages.  However,  venereal  diseases  are  not  the  only  ills 
which  have  been  disseminated  by  the  white  man.  Indeed,  if  the  pres- 
ent opinion  concerning  the  introduction  of  syphilis  into  Europe  be  true, 
it  was  one  of  the  jewels  borne  to  Spain  by  the  sailors  who  accompanied 
Columbus  on  his  first  voyage.  Smallpox  did  much  to  aid  the  Spaniard 
in  his  conquest  of  Mexico,  and  measles  and  tuberculosis  have  played 
important  roles  in  reducing  the  red  man  in  America.  According  to 
Calmette,  the  white  man  has  done  much  in  spreading  tuberculosis  to 
other  races  and  conditions  of  men. 

Hahn  points  out  that  in  countries  occupied  by  two  races  or  by 
peoples  of  different  religions,  apparent  differences  in  susceptibility  are 
due  to  material  conditions  in  life.  One  race  lives  more  hygienically 
and  more  intelligently  than  the  other.  This  is  especially  true  of  those 
infections  which  afflict  principally  the  poor  and  ignorant  classes.  In 
India  and  in  the  Philippines  plague  and  cholera  prevail  quite  exclu- 
sively among  the  natives,  while  Europeans  and  Americans  live  for  the 
most  part  in  safety.  In  the  cholera  epidemic  in  Astrakhan  in  1892, 
the  Armenians  suffered  but  little  while  the  Tartars  died  in  great  num- 
bers. Much  has  been  written  about  the  comparative  freedom  of  the 
Jew  in  Western  Europe  and  in  America  from  tuberculosis  and  this 


180  IMMUNITY 

has  been  attributed  to  racial  immunity,  but  Hahn  thinks  it  due  to 
more  hygienic  living  and  calls  attention  to  the  high  death-rate  from 
this  disease  among  the  poor,  ignorant  Jews  of  Poland  and  Galicia. 
Another  illustration  is  the  unequal  distribution  of  leprosy  among  the 
Kabyles  and  Arabs  of  Algeria.  The  former  live  in  better  houses,  select 
better  locations  for  their  homes,  are  not  so  crowded  and  are  personally 
more  clean.  The  truth  is  that  the  death-rate  from  infectious  diseases 
has  become  the  best  measure  of  intelligence.  The  more  intelligent  a 
people,  the  lower  the  death-rate. 

It  should  be  understood,  however,  that  the  death-rate  from  the 
infectious  diseases  is  a  measure  not  of  individual,  so  much  as  of  com- 
munity, intelligence.  In  this  country  the  wonderful  reduction  in  the 
death-rate  from  infectious  diseases  in  the  past  fifteen  years  has  been 
confined  largely  to  the  great  cities.  Smaller  cities,  villages  and  rural 
communities  have  improved  but  little.  The  larger  cities  are  establishing 
effective  health  departments.  Building  regulations  prevent  the  con- 
struction of  unsanitary  houses,  either  public  or  private.  Schoolchil- 
dren are  inspected  by  competent  medical  men  and  first  cases  are 
detected  and  isolated.  Proper  hospitals  for  the  infectious  diseases  are 
provided  and  scientifically  administered.  The  children  of  the  poorest 
and  most  ignorant  go  to  sanitary  school  buildings  and  when  infected, 
are  scientifically  treated.  The  health  officer  of  the  smaller  city  is  a 
joke  and  that  of  villages  and  rural  communities  exists,  for  the  most 
part,  only  in  name. 

It  was  formerly  believed  that  the  African  is  naturally  immune  to 
malaria,  but  more  recent  and  more  thorough  studies  show  that  this 
disease  is  highly  prevalent  and  fatal  among  the  children  of  that  race 
and  that  the  apparent  resistance  observed  in  the  adult  is  due  to  acquired 
immunity.  In  parts  of  Greece  and  Italy  malaria  has  been  constantly 
prevalent  for  more  than  two  thousand  years.  During  that  time  it  has 
spared  no  generation  and  in  many  localities  scarcely  any  individual, 
and  yet  no  marked  immunity  has  been  inherited.  The  young  of  recent 
generations  retain  their  susceptibility.  How  this  compares  with  that 
of  the  first  generation  subjected  to  the  infection  we  cannot  say.  How- 
ever, it  is  undoubtedly  true,  that  resistance  to  certain  specific  infections 
increases  after  many  generations  of  continuous  exposure.  The  most 
intelligent  physicians  of  Cuba  believed,  before  the  discovery  of  the 


IMMUNITY  181 

transmission  of  yellow  fever  by  the  mosquito,  that  the  natives  are 
wholly  immune  to  this  disease.  Now,  it  is  quite  evident  that  all  have 
it  lightly  in  infancy,  and  the  adult  is  protected  by  an  acquired  immunity. 
When  syphilis  first  appeared  in  Europe,  it  manifested  a  malignancy 
much  greater  than  that  now  usually  observed  in  the  white  man.  It 
is  said  to  be  still  much  less  malignant  among  the  Indians  of  Central 
America,  whose  ancestors,  far  back  beyond  the  Columbian  period, 
probably  had  the  infection.  On  the  other  hand,  people  among  whom  it 
has  recently  been  introduced,  suffer  its  full  virulence.  The  increased 
mortality  of  smallpox,  measles,  scarlet  fever  and  tuberculosis,  among 
peoples  unaccustomed  to  these  diseases,  seems  to  be  well  authenticated. 
We  must  conclude  that  increased  resistance  to  specific  infection  is  both 
inherited  and  acquired. 

Variation  in  individuals  of  the  same  species  to  a  given  infection  is 
a  most  interesting  subject  and  one  which  cannot  at  present  be  wholly 
explained.  As  a  rule,  the  more  virulent  the  infection  the  less  marked 
the  variation.  When  many  guinea-pigs  are  inoculated  with  a  fairly 
virulent  anthrax  culture  in  the  same  dosage,  all  die  about  the  same 
time.  When  rabbits  are  treated  in  the  same  way  with  anthrax,  some 
die  within  one  or  two  days,  others  live  longer  and  some  do  not  die. 
When  rabbits  are  inoculated  with  the  bacilli  of  chicken  cholera,  there 
seems  to  be  no  resistance.  The  reaction  at  the  point  of  inoculation  is 
slight,  a  general  septicemia  results  and  all  the  animals  die.  When 
guinea-pigs  are  inoculated  with  the  same  organism  there  is  a  marked 
local  reaction,  as  a  rule  there  is  no  general  infection  and  but  few  die. 
When  guinea-pigs  are  inoculated  with  a  virulent  culture  of  the  human 
tuberculosis  bacillus  all  die.  With  rabbits  only  a  small  proportion  die. 
The  water-supply  of  a  city  becomes  infected  with  cholera  or  typhoid 
bacilli.  From  5  to  20  per  cent,  of  those  who  drink  the  water  may 
develop  the  disease.  Why  does  not  this  happen  to  all?  Some  answer 
by  saying  that  the  bacilli,  being  particulate,  are  not  uniformly  dis- 
tributed through  the  water,  consequently  all  who  drink  the  water  do 
not  swallow  the  infective  agent.  All  soldiers  who  make  a  charge  in 
the  face  of  continuous  musketry  discharges  are  not  killed  or  wounded. 

There  is  much  of  truth  in  this  explanation,  but  it  is  not  altogether 
applicable.  Many  of  those  who  do  swallow  the  bacilli,  as  can  be  dem- 
onstrated by  their  presence  in  the  stools,  do  not  develop  the  disease. 


182  IMMUNITY 

Then,  of  those  who  do  develop  the  disease,  some  have  it  lightly,  others 
more  severely  and  some  fatally.  The  relative  insusceptibility  of  nurs- 
ing infants  to  diphtheria  and  certain  other  infections  is  well  known, 
and  Schick  has  shown  that  the  blood  of  many  of  them  contains  anti- 
toxin, possibly  acquired  through  the  mother's  milk.  Certainly,  no 
such  marked  variations  in  susceptibility  to  a  chemical  poison  could  be 
expected.  An  infection  must  meet  with  some  resistance  to  its  mul- 
tiplication and  this  is  not  equally  effective  in  all  individuals.  It  seems 
fair  to  conclude  from  this  that  in  all  probability  the  resisting  agent  is 
also  a  living  thing  or  some  product  or  products  of  living  things. 


CHAPTER    XXIV 


PHAGOCYTOSIS 

Phagocytes. — We  owe  our  knowledge  of  the  most  important  facts 
in  the  new  science  of  immunology  to  the  labor  and  genius  of  Metch- 
nikoff,  whose  elucidation  of  biologic  processes  we  will  follow  in  some 
detail.  In  many  forms  of  life,  from  the  simplest  unicellular  to  the 
most  complex  multicellular,  there  are  certain  cells,  one  of  whose 
functions  is  to  engulf  and  digest  other  cells.  These  eating  cells  are 
designated  by  Metchnikoff  as  "phagocytes."  The  fungi  which  devour 
fallen  wood,  dead  leaves  and  other  decaying  vegetable  matter  consist 
of  sporangia  or  clusters  filled  with  innumerable  round  spores  or  cells. 
Under  proper  conditions  these  zoospores  are  set  free  and  develop  into 
naked  masses  of  protoplasm  known  as  plasmodia  *  which  vary  in  size 
from  small  bodies  to  those  several  feet  in  length.  In  the  free  state, 
these  plasmodia  are  motile  and  they  may  engulf  and  digest  solid 
matter.  They  shun  dry,  and  seek  moist,  places.  Certain  substances 
attract  and  others  repel  them.  This  phenomenon  is  known  among 
botanists  as  chemotaxis.  Most  dead  vegetable  matter  attracts  them 
while  solutions  of  salt  and  sugar  repel  them.  In  other  words,  they  are 
attracted  by  substances  which  supply  them  with  proper  food,  and  are 
repelled  by  substances  which  harm  them.  The  former  is  known  as 
positive,  and  the  latter  as  negative,  chemotaxis.  However,  in  this 
respect  they  are  capable  within  limits  of  accommodating  themselves 
to  their  surroundings,  and  negative  chemotaxis  may  become  positive. 

These  plasmodia  can  feed  on  both  soluble  and  insoluble  sub- 
stances. In  the  latter  instance,  they  project  pseudopodia,  surround 
the  solid  and  digest  it.  This  can  be  demonstrated  by  springkling  on 
their  food  some  color  such  as  carmine.  These  plasmodia  absorb  and 
digest  not  only  dead,  but  also  living  particles.  For  instance,  they  feed 
upon  living  algae  and  the  process  of  digestion  within  the  cell  can  be 
studied.  Within  the  cells,  green  algae  can  be  seen  to  turn  brown,  then 


*  This  has  nothing  to  do  with  the  plasmodia  of  malaria. 


184  PHAGOCYTOSIS 

become  granular  and  then  disappear.  They  also  absorb  or  engulf 
motile  bacteria  which  may  for  a  while  continue  to  display  their 
motility.  Digestion  is  performed  by  means  of  an  acid  fluid,  as  can 
be  demonstrated  by  feeding  them  on  litmus  or  on  substances  colored 
with  neutral  red.  In  some  instances  at  least,  digestion  proceeds  not 
only  in  feebly  acid,  but  also  in  neutral  and  feebly  alkaline  solution. 
For  this  reason  the  digestive  ferment  is  regarded  as  a  trypsin  rather 
than  a  pepsin. 

Another  phagocyte  is  the  ameba,  which  by  means  of  its  pseudo- 
podia  surrounds  and  digests  not  only  dead  particles,  but  also  micro- 
scopic plants,  animals  and  bacteria.  Intracellular  digestion  in  these 
unicellular  animals  has  been  carefully  studied  with  most  interesting 
results.  They  take  into  their  bodies  both  dead  and  living  bacteria, 
algae  and  infusoria.  It  is  easy  to  watch  the  behavior  of  living  cells 
after  engulfment.  Some  amebas  live  exclusively  on  living  cells  and 
some  restrict  their  food  to  bacteria.  Indeed,  some  are  so  particular 
that  they  prefer  one  bacterial  species,  and  when  supplied  with  mixed 
cultures  they  devour  their  favorite,  leaving  others  unharmed.  Mouton 
studied  a  species  of  amebas  which  had  been  fed  through  many  gen- 
erations wholly  on  colon  bacilli. 

It  is  especially  worthy  of  note  that  when  colon  cultures  are  fed 
to  those  amebas,  the  bacilli  may  be  agglutinated  or  bunched  outside 
the  amebas  and  entire  clumps  are  engulfed  at  once.  The  similarity 
between  this  process  and  the  agglutination  of  typhoid  bacilli  with  the. 
serum  of  one  ill  with  this  disease  is  striking  and  significant.  One  is 
justified  in  supposing  that  in  each  case  the  phagocytes  (in  typhoid 
fever,  the  body  cells)  pour  out  a  secretion  which  prepares  the  bacilli 
for  absorption.  Of  course,  in  the  agglutination  of  typhoid  bacilli 
with  serum,  the  phagocyte  is  not  present,  but  remains  in  the  body. 
However,  agglutination  is  not  essential  and  single  bacilli  may  be 
absorbed  and  digested.  In  absorption,  the  bacteria  are  taken  into  a 
vacuole  and  the  process  of  intracellular  digestion  begins.  When  the 
bacilli  have  been  previously  stained  with  neutral  red,  they  are  seen 
to  become  cherry  red  in  the  vacuole,  showing  that  the  digestive  fluid 
is  acid.  The  ferment  is  known  as  the  ameba-enzyme.  It  may  be 
obtained  by  dissolving  or  extracting  masses  of  amebas.  It  acts  in 
feebly  acid,  neutral,  and  feebly  alkaline  solutions.  It  readily  digests 


PHAGOCYTOSIS  185 

gelatin  and  blood  fibrin,  less  markedly,  egg  albumin.  Its  optimum 
temperature  is  25  C.  (77  F.)  or  slightly  above,  but  it  acts  slowly  as 
low  as  8  C.  At  60  C.  it  is  destroyed.  When  solutions  of  this  enzyme 
are  treated  with  bacteria  killed  with  chloroform,  the  cloudy  fluid  soon 
becomes  perfectly  clear.  It  must  be  noted  that  Mouton  did  not  suc- 
ceed in  digesting  living  bacteria  with  the  extracted  enzyme,  but  they 
are  digested  in  living  amebas.  This  suggests  that  the  bacilli  are  killed 
by  one  enzyme  and  digested  by  another.  The  killing  enzyme  may  be 
poured  out  into  the  surrounding  fluid  from  the  living  cells  and  when 
the  amebas  are  killed  its  formation,  quite  naturally,  stops.  The  forma- 
tion of  the  digestive  enzyme  also  stops  when  the  amebas  are  killed 
and  the  extract  contains  only  the  excess  already  formed. 

Most  infusoria  depend,  in  part  at  least,  on  intracellular  digestion. 
Most  of  them  accomplish  this  by  acid  secretions,  while  some  supply 
feebly  alkaline  fluids.  While  protozoa  depend  largely  on  intracellular 
digestion,  this  function  is  not  wanting  in  many  multicellular  organ- 
isms. In  many  invertebrates  the  digestive  cells  of  the  intestinal  tract 
consist  wholly  of  sessile  phagocytes.  This  is  largely  true  of  sponges 
and  coelenterates.  This  is  beautifully  illustrated  in  the  siphon  sponges 
which  are  true  beasts  of  prey.  They  swallow  entire  Crustacea  which 
are  taken  into  the  alimentary  canal  where  they  are  surrounded  by, 
whole  groups  of  entodermal  phagocytes,  fusing  into  great  protoplasmic 
masses,  and  digested.  The  actinea  seize  their  victims  with  their  ten- 
tacles and  digest  them  after  absorbing  them  into  their  mesodermal 
cells.  Mesnil  has  succeeded  in  extracting  from  these  cells  an  enzyme 
which  digests  fibrin  and  coagulates  albumin  in  feebly  acid,  neutral  and 
feebly  alkaline  solutions.  The  digestion  proceeds  at  from  15  to  20  C., 
the  temperature  at  which  actinea  live,  but  in  vitro,  it  is  most  effective 
at  from  35  to  45  C.  Higher  temperature  weakens  its  activity  which  is 
wholly  arrested  at  from  55  to  60  C.  The  actino-enzyme  produces  pep- 
tone and  amino-acid.  In  these  animals,  digestion  seems  to  be  wholly 
intracellular. 

While  intracellular  digestion  is  common  in  the  intestinal  canal  of 
the  lower  invertebrates,  it  is  replaced  by  extracellular  intestinal  diges- 
tion in  the  higher  invertebrates  and  in  the  vertebrates.  The  intestinal 
epithelium  loses  its  ability  to  project  pseudopodia,  engulf  food  and 
digest  it.  These  cells  become  glands  which  pour  out  enzymes  and 


186  PHAGOCYTOSIS 

intestinal  digestion  becomes  extracellular.  However,  certain  meso- 
dermal  cells,  even  in  the  highest  mammals,  including  man,  continue  in 
the  possession  of  ameboid  movements  and  the  exercise  of  intracellular 
digestion.  The  burden  of  digestion  for  the  animal  body  as  a  whole 
rests  on  certain  glands,  but  as  a  further  protection  against  invasion  by 
foreign  proteins,  the  white  blood  cells  retain  active  movements  and 
the  ability  to  engulf  and  destroy  micro-organisms. 

Metchnikoff  has  shown  that  the  metamorphic  change  through 
which  many  insects  and  other  animals  pass  is  brought  about  by  phago- 
cytic  action.  The  tail  of  the  tadpole  is  eaten  away  by  the  white  blood 
corpuscles.  Some  of  the  tissue  changes  both  normal  and  abnormal  in, 
man  are  due  to  the  same  agents.  The  involution  of  the  uterus  after 
childbirth  is  due  to  the  absorption  and  intracellular  digestion  by  phago- 
cytes of  the  unnecessary  tissue.  The  whitening  of  the  hair  with 
advancing  age  results  from  the  consumption  of  the  pigment  by  phago- 
cytes. The  general  deterioration  of  the  brain  with  advancing  senility 
is  due  to  the  activity  of  the  neuronophages.  In  short,  the  man  who 
lives  to  die  physiologically  is  slowly  but  certainly  devoured  by  his  own 
phagocytes.  Sometimes,  however,  they  seemingly  are  not  content  to 
let  us  live  out  the  allotted  time,  and  they  fall  on  and  devour  some  part 
of  our  anatomy  prematurely.  According  to  Metchnikoff,  progressive 
muscular  atrophy  is  an  illustration  of  this  apparently  undue  greed  on 
the  part  of  our  wandering  cells.  This  must  not  lead  us  to  a  hasty  and 
rash  condemnation  of  our  eating  cells,  for  if  they  did  not  feed  on  the 
micro-organisms  which  are  frequently  entering  our  bodies,  our  lives 
would  be  even  shorter  and  more  precarious  than  they  are. 

If  some  of  its  own  blood,  or  that  of  another  individual  of  the  same 
species,  be  injected  into  the  peritoneal  cavity  of  an  animal,  it  is  readily 
absorbed  and  does  no  harm.  If  it  be  from  another  species  the  phago- 
cytes come  from  all  parts  of  the  body  and  devour  the  foreign  material. 
This  is  true  not  only  of  blood  but  of  other  foreign  cells.  Indeed,  cells 
whose  normal  habitat  is  limited  to  one  organ  or  tissue  become  foreign 
substances  when  introduced  into  another  part.  Spermatic  cells 
injected  into  the  abdominal  cavity  of  the  animal  from  which  they  are 
taken  become  the  prey  of  the  white  blood  cells.  When  foreign  material 
is  injected  into  the  abdominal  cavity,  at  first  the  white  blood  cells, 
already  there,  seem  to  be  frightened  and  run  away,  but  soon  they 


PHAGOCYTOSIS  187 

return  in  greatly  increased  numbers  and  undertake  the  destruction  of 
the  foreign  substance.  If  this  substance  be  sterile  no  great  harm  is 
likely  to  result.  The  surgeon  leaves  catgut  sutures  in  the  tissues,  but 
if  they  be  sterile  the  phagocytes  eat  them  entirely  and  no  harm  comes. 

Among  the  several  kinds  of  white  blood  corpuscles,  the  large  mono- 
nuclear  cells  are  most  effective  in  feeding  on  animal  cells,  whether 
native  or  •  foreign  to  the  body,  and  are  designated  by  MetchnikofT  as 
macrophages.  The  polynuclear  leukocytes  play  a  more  important  role 
in  bacterial  infection  and  are  denominated  microphages.  The  former 
are  able  to  engulf  and  completely  digest  a  large  number  of  cells.  If 
lymph  glands,  the  great  omentum  or  the  spleen  be  crushed,  ground  in 
a  mortar  and  extracted  with  salt  solution,  a  fine  emulsion  is  obtained, 
and  this  dissolves  the  red  corpuscles  of  various  vertebrates.  This 
hemolytic  action  is  destroyed  by  a  temperature  of  56  C.  continued  for 
one  hour,  and  at  60  C.  in  a  shorter  time.  This  thermolabile  ferment 
is  the  cytase  of  Metchnikoff,  the  alexin  of  Buchner,  and  the  comple- 
ment of  Ehrlich.  It  should  be  stated  that  the  emulsion  of  macro- 
phages contains  other  and  thermostabile  hemolytic  agents,  such  as 
fatty  acids  and  soaps,  but  with  these  we  are  not  concerned  at  present. 

Bordet  showed  that  the  ferment  obtained  from  the  macrophages 
is  a  complex  body  consisting  of  two  parts.  One  is  thermolabile,  the 
other  thermostabile.  One  combines  with  red  corpuscles  even  at  low 
temperature,  but  does  not  dissolve  them  until  the  other  enters  into  the 
reaction.  Bordet  calls  the  thermostabile  body  the  sensitizer.  It  pre- 
pares the  red  corpuscles  for  the  action  of  the  complement.  Ehrlich 
names  the  thermostabile  substance  the  amboceptor,  combining  by  one 
hand  with  the  red  corpuscle  and  by  the  other  with  the  complement. 
Bordet's  conception  is  that  the  action  of.  the  sensitizer  is  a  physical  one 
similar  to  that  of  a  mordant ;  Ehrlich's  is  that  of  a  chemical  combina- 
tion. It  is  needless  to  go  into  a  discussion  of  this  difference  since  all 
agree  that  the  ferment  consists  of  a  thermostabile  and  a  thermolabile 
part  and  that  joint  action  is  necessary  to  induce  hemolysis  or  other 
cytolysis.  The  alexin  or  complement  does  not  combine  with  the  red 
corpuscle  or  foreign  cell  directly,  and  does  so  only  through  the  sensi- 
tizer or  amboceptor.  In  his  later  papers,  Metchnikoff  retains  the  term, 
cytase,  for  the  thermolabile  body  and  adopts  the  term,  fixator,  for  the 
thermostabile  substance. 


188  PHAGOCYTOSIS 

It  must  be  evident  from  the  facts  already  stated  that  it  is  a  func- 
tion of  the  white  blood  corpuscles,  to  fall  on  invading  cells,  absorb 
and  digest  them.  By  chemotaxis  the  phagocytes  are  called  to  the  point 
of  bacterial  invasion.  The  army  of  defense  is  mobilized  by  the  blood 
and  lymph.  The  individual  leukocytes  may  pass  through  tissues, 
including  the  walls  of  vessels,  and  this  aids  in  the  movements  of  con- 
centration. When  the  foreign  protein,  which  has  found  its  way  into 
the  body,  is  dead,  the  only  question  about  it  is  the  ability  of  the  phago- 
cytes to  digest  it.  If  they  are  not  able  to  do  so  at  once,  they  may  acquire 
this  function.  When  the  foreign  protein  consists  of  living  organisms, 
there  is  a  struggle  between  defenders  and  invaders.  The  destruction 
of  the  latter  does  not  depend  solely  on  the  ability  of  the  former  to 
engulf  and  digest  their  opponents.  The  digestive  ferments  may  be 
excreted  or  poured  out  into  the  surrounding  fluid  by  the  phagocytes, 
and  at  their  death  and  dissolution  all  the  ferment  contained  within 
their  bodies  is  disseminated  throughout  the  adjacent  tissue  and  exerts 
its  destructive  action  on  the  invaders.  It  seems  that  in  giving  their 
lives  for  the  protection  of  the  body  as  a  whole,  the  leukocytes  may 
become  most  effective.  The  secretions  from  the  phagocytes  are  con- 
stantly, in  health  and  in  disease,  passing  into  the  blood,  and,  besides, 
these  cells  are  constantly  suffering  death  and  dissolution  and  in  this 
way  blood  and  serum  receive  a  constant  supply  of  germicidal  enzymes. 

Besides  the  leukocytes,  there  are  certain  fixed  cells  which  may  be 
regarded  as  phagocytes.  Such  are  connective  tissue  and  endothelial 
cells.  However,  some  of  these  are  modified  leukocytes.  For  instance, 
the  Kupffer  cells  of  the  liver  are  now  regarded  by  Metchnikoff  as  large 
mononuclear  leukocytes.  This  leaves  the  large  cells  of  the  lymph 
glands,  the  spleen  and  bone  marrow  as  fixed  phagocytes.  These  are 
regarded  as  playing  only  a  subordinate  role  in  immunity  when  com- 
pared with  the  wandering  leukocytes. 

Phagocytosis  in  Natural  Immunity. — MetchnikofFs  attention  was 
called  to  the  subject  of  phagocytosis  by  observations  on  an  infection 
in  a  small,  fresh-water  crustacean,  the  daphnia,  which  on  account  of 
its  transparency  offers  special  opportunity  for  a  study  of  this  kind. 
This  organism  is  infected  by  the  spores  of  a  certain  yeast,  which  gain 
access  to  the  body  cavity,  where,  when  unhindered,  they  multiply  in 
great  numbers  and  soon  destroy  their  host.  However,  the  invader 


PHAGOCYTOSIS  189 

meets  with  resistance,  and  when  the  numbers  are  not  too  great,  all  the 
spores  are  taken  into  leukocytes  and  digested.  When  the  spores  are 
too  numerous,  they  develop  and  pour  out  a  secretion  which  kills  and 
digests  the  leukocytes,  then  fatal  infection  follows.  In  the  trans- 
parent daphnia  all  stages  of  this  combat  can  be  followed  under  the 
microscope.  Metchnikoff  applied  this  knowledge  to  a  study  of  anthrax 
infection.  He  found  that  when  animals  naturally  immune  to  this 
organism,  such  as  dogs  and  frogs,  are  inoculated,  the  bacilli  are 
engulfed  in  leukocytes  which  speedily  gather  at  the  point  of  inocula- 
tion. On  the  other  hand,  in  highly  susceptible  animals,  such  as  guinea- 
pigs  and  mice,  phagocytosis  is  wholly  wanting  or  but  slightly  in  evi- 
dence. In  moderately  susceptible  animals,  such  as  rats  and  rabbits, 
phagocytosis  is  more  marked  and  may  or  may  not  protect,  depending 
on  the  virulence  and  number  of  the  bacilli  introduced.  Further  studies 
in  many  laboratories  have  shown  that  the  greater  the  susceptibility  of 
an  animal  to  anthrax,  the  less  markedly  does  phagocytosis  occur  on 
inoculation,  and  the  more  highly  immune  the  animal  the  more  marked 
is  the  phagocytosis.  It  is  generally  admitted  that  natural  immunity  to 
anthrax  is  due  to  phagocytic  effectiveness. 

In  the  study  of  certain  anaerobic  bacteria,  as  the  bacilli  of  tetanus, 
symptomatic  anthrax  and  malignant  edema,  interesting  facts  concern- 
ing phagocytosis  have  been  ascertained.  Paradoxical  as  it  seems,  all 
animals  have  a  natural  immunity  to  tetanus,  but  this  immunity  is  sup- 
pressed when  certain  non-pathogenic  bacteria  are  introduced  into  the 
animal  along  with  the  tetanus  bacillus.  The  injection  of  a  large 
amount  of  tetanus  bacilli  or  their  spores  into  animals  are  without 
effect  provided  there  is  no  ready-made  tetanus  toxin  injected  at  the 
same  time.  Under  this  condition,  a  large  number  of  leukocytes  collect 
at  the  point  of  inoculation  and  soon  devour  the  bacilli  and  spores.  But 
when  the  ready-made  toxin  is  present,  phagocytosis  does  not  result 
and  a  fatal  infection  follows.  The  explanation  has  been  found  to  be 
due  to  the  fact  that  the  toxin  protects  the  tetanus  bacilli  by  exerting 
a  negative  chemotaxic  effect  on  the  leukocytes.  It  holds  back  or  repels 
the  phagocytes  until  the  spores  and  bacilli  develop  and  produce  more 
toxin.  A  capillary  glass  tube  filled  with  tetanus  toxin  and  introduced 
under  the  skin  of  an  animal  remains  for  a  long  time  free  from  leuko- 
cytes, while  a  similar  tube  filled  with  bacilli  and  spores,  free  from 


190  PHAGOCYTOSIS 

toxin,  attracts  the  leukocytes.  The  bacilli  and  spores  exert  a  positive 
chemotaxic  effect  upon  leukocytes.  In  like  manner  the  presence  of 
certain  non-pathogenic  bacteria  occupies  the  activity  of  the  phago- 
cytes, giving  time  for  the  tetanus  bacillus  to  elaborate  its  toxin.  When 
this  point  is  reached,  the  bacilli  are  protected  by  their  own  secretion. 
Likewise,  if  a  culture  containing  the  spores  of  symptomatic  anthrax 
be  heated  high  enough  (80  to  85  C.)  to  destroy  any  toxin  that  may  be 
present,  and  be  injected  into  an  animal,  the  phagocytes  rush  to  the 
point  of  inoculation  and  devour  the  spores.  If,  however,  the  spores, 
free  from  toxin,  be  rubbed  up  thoroughly  with  fine  sterilized  sand  and 
particles  of  this  mixture  be  introduced  under  the  skin,  the  sand  pro- 
tects the  spores  long  enough  for  them  to  develop  toxin,  infection 
results,  and  the  animal  dies.  A  similar  experiment  has  been  made 
with  the  spores  of  malignant  edema.  If  toxin-free  spores  be  mixed 
with  agar  and  bits  of  this  be  placed  under  the  skin,  the  phagocytes 
attack  the  agar,  but  while  they  are  at  work  on  this  the  enclosed  spores 
develop,  produce  toxin  and  infect  the  animal.  If  the  bits  of  agar  after 
being  placed  under  the  skin  are  crushed  between  the  fingers,  the 
phagocytes  reach  the  spores,  devour  them  and  the  animal  is  protected. 
Certain  non-pathogenic  bacteria,  which  are  frequently  present  in  the 
soil,  protect  the  spores  of  malignant  edema. 

In  natural  immunity  to  tuberculosis,  phagocytes  develop  into  giant 
cells,  destroy  the  bacilli  and  lead  to  calcification.  When  the  spirilla 
of  relapsing  fever  are  injected  into  the  peritoneal  cavity  of  a  guinea- 
pig,  they  are  devoured  by  phagocytes.  In  animals  naturally  immune 
to  certain  cocci — gonococcus,  pneumococcus,  streptococcus  and  staphy- 
lococcus — phagocytosis  is  in  evidence.  Natural  immunity  to  pathoy 
genie  organisms  other  than  bacteria,  such  yeasts,  moulds,  trypano- 
somes  and  protozoa,  is  apparently  largely  due  to  phagocytic  activity. 

As  has  been  stated,  Metchnikoff  holds  that  the  polynuclear  leuko- 
cytes, which  he  calls  microphages,  play  the  important  role  in  the  bac- 
terial diseases.  The  eosinophils  also  are  capable  of  taking  in  and 
digesting  bacteria.  This  teaching  is  so  fully  accepted  that  a  marked 
increase  in  polynuclear  leukocytes  is  taken  as  an  indication  of  bacterial 
infection.  Microphages  are  transported  from  one  part  of  the  body 
to  another  in  blood  and  lymph,  and  by  means  of  their  pseudopodia, 
they  have  independent  movements.  Under  the  microscope  they  can  be 


PHAGOCYTOSIS  191 

seen  projecting  their  pseudopodia,  surrounding  and  engulfing  bacteria. 
The  bacterium  is  taken  into  a  vacuole  filled  with  clear  fluid.  If  the 
bacterium  be  motile  its  movements  may  continue  in  the  vacuole,  but 
soon  active  movement  ceases.  Vibrios  crumble  into  granules  and 
finally  disappear.  Bacilli  become  pale  and  transparent,  then  are  seen 
only  in  shadow  and  finally  this  is  lost.  Cocci  swell  up,  become  trans- 
parent and  then  are  lost  to  sight.  However,  some  bacteria,  such  as  the 
tubercle  and  leprosy  bacilli,  remain  in  the  microphage  quite  indefi- 
nitely without  recognizable  change.  The  same  is  true  of  certain 
spores.  In  these  cases,  there  is  no  digestion,  but  the  body  is  protected 
from  the  multiplication  of  the  organism.  Phagocytes  take  up  litmus 
granules  which  show  no  change  in  color  after  inclusion,  but  bacilli 
stained  with  neutral  red  become  cherry  red  in  the  vacuole,  showing 
that  the  fluid  is  feebly  acid.  While  this  is  the  rule,  in  some  phago- 
cytes, as  in  the  giant  cells  containing  tubercle  bacilli,  the  reaction  is 
plainly  alkaline.  There  can  be  no  question  that  phagocytes  engulf  and 
finally  destroy  bacteria.  A  phagocyte,  which  has  recently  engulfed  a 
living  bacillus,  when  brought  in  a  hanging  drop  under  the  microscope, 
soon  dies  itself  and  the  liberated  bacterium  may  begin  to  multiply, 
but  when  the  inclusion  has  continued  for  a  longer  time,  the  liberated 
bacterium  does  not  grow.  There  has  been  some  discussion  over  the 
question  of  the  identity  of  the  digestive  ferments  of  the  mononuclear 
and  the  polynuclear  phagocytes.  A  priori  we  should  expect  them  to 
be  different,  and  the  weight  of  evidence  supports  this  view.  Exudates 
especially  rich  in  mononuclear  leukocytes  are  active  as  hemolytic 
agents  but  have  only  feeble  germicidal  action,  while  those  rich  in 
polynuclear  leukocytes  have  no  hemolytic  action,  but  are  powerful 
bactericides.  Is  this  difference  in  both  the  complement  (alexin  or 
cytase)  and  the  fixator  (sensitizer  or  amboceptor)  or  in  the  latter 
only?  This  question  has  given  rise  to  some  marked  differences  of 
opinion  but  a  positive  conclusion  is  not  justified  by  any  undisputed 
evidence  and  we  will  leave  it  for  future  investigators  to  answer. 

In  concluding  this  part  of  our  subject,  it  must  be  admitted  that 
Metschnikoff  and  those  who  have  labored  in  the  same  field  have 
demonstrated  that  phagocytosis  is  an  important  factor  in  natural 
immunity. 


192  PHAGOCYTOSIS 

Phagocytosis  in  Acquired  Immunity. — Metschnikoff  has  shown 
that  acquired  immunity  is  largely  due  to  stimulated  phagocytosis. 
This  is  true  whether  the  immunity  be  due  to  one  attack  of  the  disease 
or  to  vaccination.  A  rabbit  which  has  been  immunized  to  anthrax 
shows  a  more  marked  phagocytosis  on  inoculation  with  a  virulent  cul- 
ture than  does  a  fresh  animal.  In  the  latter  there  is  only  a  slight 
serous  exudate  at  the  point  of  inoculation,  while  in  the  former  there 
is  an  abundant  accumulation  of  leukocytes,  which  ingest  and  digest  the 
bacilli.  A  drop  of  this  exudate  injected  into  an  animal  highly  suscep- 
tible to  anthrax,  a  guinea-pig  or  mouse,  usually  results  in  fatal  infec- 
tion, showing  that  the  included  bacilli  are  not  immediately  killed. 
Some  hours  after  inoculation  of  an  immunized  animal,  microscopic 
examination  of  the  exudate  shows  no  free  bacilli.  All  are  included  in 
the  leukocytes  and  some  seem  normal  while  others  show  granulation 
and  others  degenerative  changes.  Similar  observations  have  been 
made  on  other  animals  immunized  to  anthrax  by  vaccines.  The  phago- 
cytes are  stimulated  by  the  introduction  of  the  attenuated  bacilli  of  the 
vaccines,  and  finally  become  strong  enough  to  contend  successfully 
with  those  of  full  virulence. 

Pfeiffer  has  shown  that  if  guinea-pigs  be  highly  immunized  to  the 
cholera  vibrio  by  repeated  intraperitoneal  injections,  the  clear  peri- 
toneal fluid  dissolves  these  organisms  much  as  water  dissolves  sugar 
or  salt.  There  is  no  phagocytosis  in  evidence.  In  fact,  the  peritoneal 
fluid  is  quite  free  from  leukocytes.  This  is  known  as  Pfeiffer's  phe- 
nomenon, and  it  has  been  held  by  many  that  it  overthrew  Metschni- 
koff's  theory  of  the  importance  of  phagocytosis  in  acquired  immunity. 
In  fact,  this  phenomenon  has  divided  immunologists  into  two  camps, 
the  holders  of  the  humoral,  and  those  of  the  cellular  theory.  Metsch- 
nikoff explains  Pfeiffer's  phenomenon  as  follows :  The  repeated  injec- 
tions of  the  vibrio  into  the  peritoneal  cavity  have  accumulated  in  that 
viscus  many  phagocytes  which  have  been  injured  and  have  given  up 
their  contents,  including  their  digestive  enzyme,  to  the  surrounding 
fluid.  In  fact,  Metschnikoff  has  demonstrated  masses  of  these  dead 
leukocytes  on  the  peritoneal  walls  and  the  omentum.  This  destruction 
and  dissolution  of  the  phagocytes  he  designates  phagolysis.  The  agent 
in  the  fluid  which  dissolves  the  vibrios  is  the  enzyme  from  the  injured 
leukocytes.  The  solvent  action  proceeds  extracellularly,  but  the  sol- 


PHAGOCYTOSIS  193 

vent  agent  is  of  intracellular  origin.  Furthermore,  he  has  shown  that 
the  phagolysis  can  be  prevented,  and  when  this  is  done  the  peritoneal 
fluid  remains  rich  in  leukocytes  and  phagocytic  action  is  easily  dem- 
onstrated under  the  microscope.  Still  further,  Levaditi  has  shown 
that  phagolysis  may  occur  in  other  parts  of  the  body.  If  the  cholera 
vibrio  be  injected  into  the  circulation  of  a  highly  immunized  guinea- 
pig,  the  phagocytes  practically  disappear  from  the  peripheral  blood. 
On  sectioning  the  lungs  they  are  found  in  clumps  and  evidently 
injured.  About  them  are  seen  masses  of  the  vibrio  undergoing  diges- 
tive changes.  Positive  chemotaxis  still  manifests  its  influence  and 
brings  the  phagocytes  and  bacilli  together  at  the  place  where  the 
former,  in  undergoing  dissolution,  pour  out  a  secretion  which  is  fatal 
to  the  latter. 

If  cholera  vibrios  be  injected  into  the  anterior  chamber  of  the  eye 
of  a  highly  immunized  guinea-pig,  a  place  where  there  has  been  no 
phagolysis,  the  phagocytes  concentrate  here  and  phagocytosis  may  be 
demonstrated. 

Further  elucidation  of  this  subject  seems  unnecessary.  It  is  evi- 
dent that  in  acquired  immunity  there  is  increased  activity  and  effec- 
tiveness on  the  part  of  the  phagocytes  in  the  destruction  of  the  invad- 
ing organism,  which  may  be  destroyed  by  intracellular  or  extracellular 
digestion.  In  either  case  the  destructive  agent  is  supplied  by  the 
phagocytes.  Metschnikoff  holds  that  in  the  body  intracellular  digestion 
is  the  rule  and  that  extracellular  destruction  plays  only  a  subordinate 
role. 

Phagocytosis  in  Injuries  and  Disease. — In  this  section  we  continue 
to  follow  the  teachings  of  Metschnikoff.  In  inflammation  there  is  an 
accumulation  of  phagocytes  at  the  point  of  injury.  When  the  injury 
is  aseptic,  the  functions  of  the  phagocytes  are  to  remove  the  injured 
body  cells  and  to  repair  the  tissue.  In  septic  wounds  the  additional 
duty  of  destroying  the  foreign  cells  falls  on  the  phagocytes.  In  the 
lower  animals  which  possess  neither  nerves  nor  blood  vessels,  the 
motile  connective-tissue  cells  devour  the  invading  organisms.  In  the 
higher  animals  the  process  is  more  complicated.  Through  nerve  stim- 
ulation, the  blood  vessels  of  the  injured  part  are  dilated,  phagocytes 
from  distant  parts  of  the  body  are  brought  to  the  locality  and  pass 


194  PHAGOCYTOSIS 

through  the  walls  of  the  vessels.  Inflammatory  transudates  which 
contain  but  few  leukocytes  are  the  exceptions.  They  occur  only  when 
the  injury  is  so  slight  that  great  activity  is  not  needed  or  at  the  other 
extreme  when  it  is  so  great  or  the  infection  is  so  virulent  that  repair 
and  resistance  are  impossible.  The  mononuclear  cells,  the  macro- 
phages,  may  become  fixed  connective  tissue  and  form  scar-tissue.  The 
polynuclear  cells,  the  microphages,  do  not  serve  this  purpose. 

There  are  inflammations  which  are  due  to  soluble  irritants  with- 
out cellular  elements.  In  these  instances  the  phagocytes  assemble  and 
feed  on  the  fluid.  Strictly  speaking,  there  are  probably  but  few 
wounds  absolutely  free  from  bacteria,  but  when  these  are  few  in 
number  and  non-virulent,  they  are  soon  destroyed  by  the  phagocytes 
and  healing  by  first  intention  results. 

Fehleisen  has  studied  phagocytosis  in  erysipelas.  In  the  initial 
stage  the  streptococci  are,  for  the  most  part,  free ;  in  the  second,  many 
are  included  in  phagocytes;  in  gangrenous  areas  there  are  but  few 
leukocytes  and  these  show  degenerative  changes ;  in  healed  areas  there 
are  but  few  free  cocci,  many  in  leukocytes,  also  many  macrophages. 
Beyond  the  inflammatory  area  the  cocci  are  free;  on  the  edge  many 
cocci  are  included  in  phagocytes ;  in  the  third  zone  the  cocci  are  want- 
ing and  there  is  marked  small-cell  infiltration.  In  pneumonia  the 
favorable  progress  of  the  disease  is  indicated  by  an  increase  in  the 
sputum  of  phagocytes  containing  pneumococci.  Immediately  after  a 
slight  leakage  from  a  diseased  appendix  all  the  bacteria  are  free,  with 
time  more  and  more  are  found  in  leukocytes,  and  in  case  of  recovery, 
all  are  disposed  of  in  this  way. 

Phagocytosis  is  in  evidence  in  certain  systemic  infections,  for 
instance,  relapsing  fever.  This  has  been  studied  in  apes.  The  first 
febrile  stage  lasts  a  few  days  and  generally  ends  in  permanent  recov- 
ery. Several  apes  were  killed  at  different  hours  in  the  febrile  stage. 
Before  the  fever,  the  spirilla  may  be  abundant  in  the  blood,  but  with 
the  rise  in  temperature  they  can  no  longer  be  detected  in  the  peripheral 
circulation.  At  the  crisis,  the  polynuclear  cells  of  the  spleen  are  filled 
with  the  spirilla,  some  of  which  seem  quite  normal  while  others  show 
degenerative  changes.  A  fresh  ape  inoculated  with  these  cells  develops 
the  disease,  showing  that  at  least  some  of  the  included  spirilla  are  still 
alive  and  virulent.  An  examination  of  the  spleen  after  recovery  shows 


PHAGOCYTOSIS  195 

all  the  spirilla  markedly  changed  and  inoculation  with  this  material 
does  not  induce  the  disease.  It  is  true  that  the  serum  of  one  in  the 
febrile  stage  of  relapsing  fever  is  markedly  bactericidal  to  the  spiril- 
lum, but  this  is  due  to  the  destruction  of  the  leukocytes  and  the  pass- 
ing of  the  enzyme  into  solution.  There  seems  no  doubt  that  recovery 
from  relapsing  fever  is  due  to  phagocytic  activity. 

Uhlenhuth  found  that  phagocytosis  is  responsible  for  the  sponta- 
neous healing  of  experimental  syphilis  in  rabbits.  Like  success  is  not 
in  evidence  in  this  disease  in  man,  although  here  also  phagocytosis 
seems  to  deserve  credit  for  the  healing  of  specific  lesions  so  far  as 
they  spontaneously  occur. 

The  fact  that  the  plasmodia  of  malaria  are  engulfed  by  the  phago- 
cytes of  the  blood,  spleen  and  liver  is  well  known.  Many  of  them  are 
undoubtedly  destroyed  in  this  process,  but  unfortunately  many  escape 
to  multiply  and  continue  to  induce  their  deleterious  effects. 

Rindfleisch  holds  that  phagocytes  are  more  or  less  effective  in  the 
removal  of  gouty  deposits. 


CHAPTER    XXV 


SPECIFIC    PRECIPITINS 

History. — In  1897  Kraus  discovered  that  the  blood  serum  of  ani- 
mals immunized  to  a  given  bacterium  gives  a  precipitate  when  mixed 
with  a  germ-free  nitrate  of  a  culture  of  that  organism.  Further  study 
showed  that  this  reaction  is  specific.  Cholera  serum  precipitates  only 
cholera  filtrates ;  typhoid  serum  only  typhoid  filtrates,  etc.  Two  years 
later  Tchistowitsch  and  Bordet  ascertained  that  this  is  a  general  pro- 
tein reaction.  A  rabbit  which  has  had  several  injections  of  horse 
serum  yields  a  serum  which  precipitates  horse  serum  and  no  other. 
One  treated  with  cow's  milk  furnishes  a  serum  which  precipitates 
cow's  milk  and  no  other.  One  treated  with  the  white  of  the  hen's  egg 
precipitates  egg  albumin  and  no  other  protein.  This  test  is  now  used 
practically  in  the  identification  of  blood  stains,  in  the  detection  of 
mixed  meats  and  in  the  study  of  the  blood  relationship  of  animals. 

If  a  blood  stain  be  dissolved  in  salt  solution  and  then  mixed  with 
the  blood  serum  of  a  rabbit  which  has  been  repeatedly  treated  with 
human  blood,  a  precipitate  will  form  if  the  stain  is  human  blood.  If 
a  Hamburger  steak  be  extracted  with  water,  the  clear  filtrate  will  be 
precipitated  with  the  blood  of  an  animal  which  has  been  treated  with 
horse's  blood  provided  the  steak  contains  horse  meat.  The  meat  of 
any  other  animal  in  the  steak  can  be  detected  in  the  same  way.  If 
the  steak  contains  beef  and  horse  meat,  its  extract  will  precipitate  the 
serum  of  an  animal  treated  with  extract  of  horse  meat  also  the  serum 
of  one  which  has  been  treated  with  an  extract  of  beef.  The  serum 
of  a  rabbit  treated  with  human  blood  will  give  a  marked  precipitate 
even  in  a  high  dilution  of  human  and  a  slighter  one  in  undiluted  chim- 
panzee's blood  serum.  This  supplies  a  method  of  detecting  and  iden- 
tifying different  proteins  in  quantities  too  small  to  be  detected  in  any 
other  way. 

The  Precipitinogen. — The  substance  which  is  injected  into  the  ani- 
mal is  known  as  the  precipitinogen  (producer  of  the  precipitin).  Pre- 
cipitinogens  are  bacterial,  vegetable,  and  animal.  A  culture  of  the 


198  PRECIPITINS 

typhoid  bacillus,  preferably  one  several  weeks  old,  is  filtered  through 
porcelain,  in  order  to  free  it  from  the  bacterial  cells,  then  every  third 
or  fourth  day  some  of  the  filtrate  is  injected  into  a  rabbit.  Some  days 
after  the  last  injection,  serum  obtained  from  this  rabbit  precipitates 
the  typhoid  filtrate  and  that  of  no  other  bacterium.  Other  precipi- 
tinogens  are  used  in  like  manner  with  like  result.  The  thing  in  the 
bacterial  culture  or  other  fluid,  which  produces  this  effect,  has  never 
been  isolated.  We  only  know  that  all  precipitinogens  are  albuminous 
substances,  or  derivatives  of  these,  and  that  no  fat,  carbohydrate  or 
crystalloid  has  such  action.  Some  precipitinogens  contain  only  simple 
proteins  and  these  in  small  amounts,  as  is  shown  by  the  application 
of  tests  for  proteins. 

The  Precipitins. — The  substance  in  the  immune  serum  is  known  as 
a  precipitin.  In  the  sera  of  certain  animals,  which  have  had  no 
treatment,  there  are  natural  precipitins.  The  serum  of  the  untreated 
ox,  undiluted,  precipitates  many  bacterial  filtrates.  Normal  goat's 
serum  gives  precipitates  with  the  sera  of  rabbits  and  dogs.  These 
normal  precipitins  do  not  interfere  with  our  tests  because  (1)  they 
are  not  specific  and  (2)  they  do  not  give  the  precipitates  in  high 
dilutions.  Not  every  animal  produces  precipitins.  The  best  laboratory 
animal  for  the  production  of  precipitins  is  the  rabbit.  It  is  best  in 
case  of  blood  tests  not  to  select  an  animal  closely  related  with  that 
from  which  the  precipitinogen  comes.  The  blood  of  one  animal  will 
not  develop  a  precipitin  in  another  of  the  same  species.  The  precipi- 
tinogen may  be  administered  intra-abdominally,  subcutaneously  or 
intravenously.  Administration  by  the  mouth  produces  a  precipitin 
only  when  for  some  reason  the  precipitinogen  is  absorbed  undigested. 
This  may  result  from  overfeeding  and  easily  happens  in  the  young. 
Puppies,  kittens,  and  rabbits,  up  to  ten  days  old,  frequently  absorb 
unchanged  proteins  from  the  alimentary  canal  and  this  leads  to  the 
production  of  precipitins.  It  has  been  found  in  a  few  instances  that 
the  serum  of  infants  precipitates  cow's  milk.  This  indicates  that  the 
casein  of  the  food  has  been  absorbed  undigested.  It  is  possible  that  this 
is  a  factor  in  the  causation  of  cholera  infantum.  Especially  is  milk 
partly  changed  by  peptonizing  bacteria  likely  to  be  absorbed  without 
digestion. 


PRECIPITINS  199 

The  tissue  in  which  the  precipitin  is  formed  is  evidently  not  the 
same  in  all  cases.  It  depends  on  the  nature  of  the  precipitinogen  and 
the  avenue  of  its  introduction.  When  a  foreign  protein  is  introduced 
parenterally,  it  has  a  predilection  for  certain  tissues  and  this  is  dif- 
ferent for  different  proteins.  We  only  know  at  present  that  precipitins 
are  formed  in  organs  rich  in  leukocytes.  The  mononuclear  cell  is 
believed  to  be  active  in  this  function.  It  is  probable  that  the  endo- 
thelial  cells  of  the  blood  vessels  also  have  this  function. 

The  precipitin  can  be  thrown  down  in  serum  by  one-third  satura- 
tion with  ammonium  sulphate  and  seems  to  be  contained  in  the 
euglobulin  fraction.  Attempts  to  obtain  a  protein-free  precipitin  have 
failed;  indeed,  I  think  it  highly  probable  that  the  precipitin  is  a  pro- 
tein. When  heated  to  70  degrees  the  serum  no  longer  reacts  with  the 
precipitinogen. 

The  Precipitate. — This  results  from  a  reaction  between  the  pre- 
cipitinogen and  the  precipitin.  In  case  of  bacterial  nitrates,  the  precipi- 
tate does  not  form  directly  on  adding  the  precipitin  to  the  precipi- 
tinogen and  it  is  customary  to  allow  the  mixture  to  stand  at  incubator 
temperature  for  from  two  to  twenty-four  hours.  The  rapidity  and 
abundance  of  the  formation  of  the  precipitate  depend  on  the  richness 
of  the  fluids  in  their  respective  active  constituents.  With  animal  pre- 
cipitinogens  the  precipitate  may  appear  immediately  on  the  mixture  of 
the  fluids.  Precipitation  takes  place  in  neutral,  feebly  alkaline  and 
feebly  acid  solutions.  When  the  acidity  is  due  to  organic  acid  or  acid 
salt,  the  action  is  promoted.  In  the  complete  absence  of  inorganic 
salts  the  reaction  fails.  The  precipitate  consists  essentially  of  pro- 
tein. It  contains  no  carbohydrate  group,  is  insoluble  in  mineral  acid 
and  alkali,  and  is  highly  resistant  to  the  digestive  ferments.  There 
seems  no  doubt  that  the  bulk  of  the  precipitate  is  derived  from  the 
precipitin.  Pick  employed  a  precipitinogen  which  did  not  give  the 
biuret  reaction  and  with  this  obtained  a  voluminous  albuminous  pre- 
cipitate. Welch  and  Chapman  obtained  with  a  precipitinogen  which 
contained  only  1  mg.  of  protein,  a  precipitate  which  contained  25.1 
mg.  of  protein.  Evidently,  in  these  cases,  the  bulk  of  the  precipitate 
must  come  from  the  serum.  However,  this  is  not  always  true  since 
the  bulk  of  the  precipitate  produced  with  lactosera  consists  of 
casein.  It  is  probable  that  in  many  instances  substances  other  than  the 


200  PRECIPITINS 

precipitinogen  and  the  precipitin  are  carried  down  mechanically.  When 
a  new  dose  of  precipitinogen  is  injected  into  an  animal  whose  blood 
already  contains  the  corresponding  precipitin,  the  amount  of  the  latter 
is  for  a  time  markedly  decreased.  This  leads  to  the  inference  that  the 
union  between  precipitinogen  and  precipitin  takes  place  in  the  body, 
but  there  is  no  evidence  that  a  precipitate  is  formed  in  vivo. 

That  both  factors  enter  into  the  formation  of  the  precipitate  quan- 
titatively is  known,  but  it  is  not  known  whether  or  not  the  whole  of 
each  factor  exists  in  the  product,  nor  is  it  known  whether  the  reaction 
is  a  physical  or  a  chemical  one.  Evidently  the  presence  of  electro- 
lytes is  essential  to  the  reaction.  Quantitatively  the  reaction  is  spe- 
cific. The  serum  of  animals  immunized  to  one  strain  of  the  colon 
bacillus  precipitates  the  filtrate  from  this  strain  in  higher  dilution  than 
it  does  the  filtrate  from  other  strains,  and  there  may  be  strains  of  the 
colon  bacillus  whose  filtrates  it  will  not  precipitate  at  all.  It  is  quite 
certain  that  the  precipitation  of  filtrates  agrees  with  the  agglutination 
of  the  living  bacilli.  It  is  difficult  not  to  believe  that  the  specificity 
of  both  these  reactions,  precipitation  and  agglutination,  is  due  to  the 
chemical  structure  of  the  protein  molecule  and  that  both  are  due  to 
definite  cleavage  of  this  molecule  in  the  process  of  parenteral  digestion. 


CHAPTER    XXVI 


AGGLUTINATION 

History. — In  1889  Charin  and  Roger  in  studying  the  action  of  the 
serum  of  sick  and  immunized  animals  on  homologous  bacteria, 
observed  that  the  Bacillus  pyocyaneus  behaved  peculiarly  when  placed 
in  the  serum  of  an  animal  immunized  to  this  organism.  In  the  serum 
of  a  normal  rabbit,  this  bacillus  grows  as  it  does  in  beef-tea,  form- 
ing an  opaque  culture,  while  in  the  serum  of  an  animal  immunized  to 
it,  it  forms  floccules  which  soon  subside  leaving  a  clear  supernatant 
fluid.  Two  years  later,  Metschnikoff  noticed  that  the  vibrio  which 
bears  his  name  behaves  in  a  similar  manner.  He  recorded  this  obser- 
vation as  follows: 

In  the  blood  and  serum  of  non-vaccinated  guinea-pigs,  the  vibrio  develops 
as  it  does  in  ordinary  liquid  media,  the  individual  organisms  retaining  their 
motility  and  remaining  distinct,  one  from  the  other.  On  the  other  hand,  in 
the  blood  and  serum  of  vaccinated  animals  the  vibrios  become  immobile,  and 
form  smaller  or  larger  floccules  which  float  in  the  liquid. 

In  1893  Issaeff,  and  later  he  and  Ivanoff  observed  the  same  phe- 
nomenon and  described  it  as  follows : 

In  the  blood  serum  of  healthy,  non-immunized  guinea-pigs  the  vibrio  develops 
rapidly,  and  after  from  four  to  five  hours  at  37°  there  is  a  uniform  cloudiness 
throughout  the  fluid,  while  the  surface  is  covered  with  a  scum;  but  in  immune 
serum,  the  microbes  sink  to  the  bottom  of  the  tube,  while  the  supernatant  fluid 
remains  clear.  This  condition  continues  for  from  eight  to  nine  days,  and  it 
is  not  until  the  tenth  day  that  the  culture  becomes  cloudy  and  a  scum  appears 
on  the  surface. 

These  observations  attracted  no  attention  and  in  all  probability  their 
significance  was  not  appreciated  by  the  observers  themselves.  In 
1896,  Gruber  and  Durham  ascertained  that  this  reaction  is  specific. 
Each  bacterium  is  clumped  by  the  serum  of  animals  which  have  been 
inoculated  with  it  and  not  by  other  sera.  They  suggested  that  the 
phenomenon  be  designated  as  "agglutination"  and  that  it  would  prove 


202  AGGLUTINATION 

serviceable  in  the  identification  of  bacteria.  A  given  bacterium  is  the 
typhoid  bacillus  if  it  is  agglutinated  by  the  properly  diluted  serum  of 
an  animal  immunized  to  this  organism.  If  an  unknown  culture  is  not 
agglutinated  by  the  serum  of  an  animal  immunized  to  the  cholera 
bacillus,  the  culture  does  not  contain  this  organism.  I  have  carefully 
read  the  original  paper  of  Gruber  and  Durham  and  fail  to  find  therein 
any  reason  for  concluding  that  these  investigators  at  that  time  had 
any  idea  that  the  phenomenon  which  they  were  investigating  was  soon 
to  become  one  of  the  most  certain  and  easily  applicable  methods  for 
the  diagnosis  of  typhoid  fever.  It  is  true  that  they  speak  of  the 
serum  test  as  a  diagnostic  measure,  but  from  the  context  it  is  plainly 
evident  that  by  the  term  diagnosis  they  mean  the  specific  and  positive 
identification  of  a  suspected  bacterium.  A  few  months  after  the  pub- 
lication of  this  paper  of  Gruber  and  Durham,  Widal  demonstrated  the 
value  of  this  reaction  in  the  diagnosis  of  typhoid  fever. 

Factors. — It  is  evident  that  in  such  a  reaction  as  that  observed  in 
agglutination  there  must  be  two  factors.  One  of  these,  designated  the 
agglutinin,  is  found  in  the  serum,  and  the  other,  known  as  the  agglutin- 
able  substance,  exists  in  the  bacterial  culture.  The  product  of  the 
reaction  is  known  as  the  agglutinate.  The  serum  of  certain  normal 
animals  has  a  slight  agglutinating  action  on  certain  bacteria,  notably 
typhoid  and  colon  bacilli.  The  normal  serum  of  the  horse,  dog, 
donkey,  and  rabbit,  in  an  undiluted  state,  agglutinates  typhoid  cul- 
tures. Some  effect  may  be  observed  when  the  serum  is  diluted  1 :  30. 
The  serum  of  a  man,  who  has  never  had  typhoid  fever,  may  agglutin- 
ate typhoid  cultures  when  the  dilution  is  not  higher  than  1 :30.  The 
period  in  the  progress  of  typhoid  fever  when  marked  agglutination 
manifests  itself  varies  widely.  Usually  it  is  not  before  the  seventh 
day,  but  it  may  occur  as  early  as  the  second  day,  and  it  may  be  delayed 
until  the  second  week  and  in  rare  cases  even  later.  Likewise  the  dis- 
appearance of  the  reaction  after  recovery  is  variable.  It  may  fail 
within  ten  days  after  the  loss  of  the  fever,  and  it  has  been  known  to 
continue  for  years.  In  intensity  the  reaction  is  variable  and  bears  no 
indication  of  the  severity  or  seriousness  of  the  disease.  There  are 
many  ways  in  which  the  phenomenon  may  be  observed  and  measured. 
One  recommended  by  Widal  and  Sicard  and  much  employed  is  the 
following : 


AGGLUTINATION  203 

A  number  of  small  diameter  tubes  each  containing  1,  2,  3,  4,  or  5  c.c.  of 
bouillon,  are  kept  on  hand.  When  a  test  is  to  be  made,  one  adds  a  drop  of 
the  serum  to  each  of  these  tubes  and  then  inoculates  each  with  a  typhoid  cul- 
ture. The  tubes  are  then  kept  at  incubator  temperature  for  from  four  to  six 
hours.  At  the  expiration  of  this  time  it  may  be  seen  at  a  glance  in  which  tubes 
agglutination  has  taken  place,  since  these  will  be  unclouded  and  the  floccules 
will  be  seen  on  the  bottom.  The  first  tube  has  a  dilution  of  1 :  20 ;  the  second, 
1 : 40,  etc. 

Johnston  was  the  first  to  show  that  a  drop  of  blood  allowed  to 
dry  on  non-absorbent  paper,  may  be  transported  any  distance  and 
kept  indefinitely  and  still  be  capable  after  solution  in  water  of  giving 
the  agglutination  test.  However,  accuracy  in  dilution  is  not  reached. 
The  reaction  may  be  observed  in  a  hanging  drop  under  the  microscope 
when  only  one  drop  of  blood  is  available. 

Agglutinins  exist  not  only  in  the  blood,  but  in  other  fluids  of  the 
body.  The  agglutinating  power  of  the  urine  in  the  same  individual 
is  variable  not  only  from  day  to  day,  but  from  hour  to  hour,  and  is 
always  feeble  compared  with  that  of  the  serum.  Serum  obtained  by 
blisters  has  a  relatively  high  agglutinating  value.  That  of  the  bile  is 
marked.  Pus  from  typhoid  abscesses  markedly  agglutinates.  Agglu- 
tinins may  pass  from  the  mother  to  the  fetus  and  to  the  nursing  child. 
Typhoid  serum  may  be  treated  with  formaldehyd  in  40  per  cent,  solu- 
tion and  kept  quite  indefinitely  without  loss  of  its  agglutinating 
property.  However,  the  use  of  antiseptics  is  not  necessary  to  preserve 
agglutinating  sera.  A  highly  active  serum  will  retain  its  agglutin- 
ative action  after  it  has  become  putrid  from  bacterial  contamination. 
Dilute  mineral  acids  decrease  the  agglutinating  property  of  typhoid 
sera,  but  when  the  contact  has  not  been  prolonged,  full  activity  may 
be  restored  by  neutralization.  Alkalies  act  similarly.  App  arently  the 
agglutinins  are  not  altered  by  either  pepsin  or  trypsin.  In  experimental 
animals,  sera  can  be  obtained  which  will  agglutinate  typhoid  bacilli 
in  dilutions  as  high  as  1 :  1,000,000  and  colon  bacilli,  1 :  2,000,000. 

Quantitatively  the  agglutinins  are  specific,  but  in  order  to  be  so 
considered  they  must  be  active  in  high  dilutions.  A  positive  diagnosis 
of  typhoid  fever  should  not  be  made  unless  the  serum  acts  decidedly 
in  a  dilution  not  less  than  1 :  50,  and  even  in  this  dilution  there  is  a 
rare  chance  of  mistake.  A  paratyphoid  serum  may  agglutinate  typhoid 


204  AGGLUTINATION 

bacilli  in  a  dilution  of  1:  1,000;  or  a  typhoid  serum  may  act  in  like 
dilution  on  a  paratyphoid  bacillus.  In  making  a  clinical  diagnosis  such 
a  mistake  would  be  of  little  or  no  importance,  but  in  the  identification 
of  a  bacterium  it  would  be  important.  According  to  Paltauf  the  fol- 
lowing dilutions  are  necessary  for  the  positive  identification  of  the 
named  bacteria:  plague  bacillus,  1:  1,000;  typhoid  and  cholera  bacilli, 
1 :  10,000.  The  active  substance  in  the  serum,  the  agglutinin,  is 
undoubtedly  a  globulin.  It  is  inactivated  at  temperatures  which  range 
from  75  to  90  C.  in  different  sera. 

The  active  constituent  of  the  culture,  the  agglutinable  substance, 
is  not,  in  my  opinion,  an  essential  constituent  of  the  bacterial  cells, 
but  consists  of  one  or  more  proteins  closely  associated  with  the  bac- 
terial cells.  It  may  be  a  protein  already  split  off  from  the  bacterial 
pabulum  in  the  culture  medium  preparatory  to  absorption,  or  it  may 
be  an  excretory  product.  The  reasons  for  this  belief  may  be  briefly 
stated  as  follows: 

1.  Agglutination  does   not   destroy  the  viability  or  virulence  of 
bacteria;  therefore,  the  reaction  does  not  disrupt  the  living  bacterial 
cell. 

2.  Thoroughly  washed  typhoid  bacilli  are  not  agglutinable. 

3.  When  typhoid  bacilli  are  thoroughly  shaken  in  salt  solution  so 
as  to  remove  the  flagellae  and  the  bacilli  are  deposited  in  a  centrifuge, 
the  emulsion  of  flagellae  is  agglutinable. 

4.  Cholera  bacilli,  as  shown  by  Neufeld,  when  shaken  with  1  per 
cent,  alkali,  which  does  not  dissolve  the  cells  but  washes  away  the 
adherent  matter,  the  cleansed  cells  are  not  inagglutinable,  but  when 
injected  into  animals  they  produce  no  agglutinin. 

Agglutination  and  precipitation  are  like  phenomena.  When  a 
bacterial  culture  is  filtered,  some  of  the  proteins  adherent  to  the  bac- 
terial cells  pass  into  solution  and  constitute  the  precipitinogen,  some 
of  the  same  class  of  near-cell  proteins  remain  in  close  connection  with 
the  cells  and  constitute  the  agglutinable  substance  or  the  agglutinogen. 
Inorganic  salts  are  essential  to  agglutination.  The  reaction  is  that  of 
a  colloid  and  the  specificity  is  due  to  the  chemical  structure  of  the 
proteins  entering  into  the  reaction.  The  agglutinable  substance  is 


AGGLUTINATION  205 

shaped  and  its   chemical   structure  determined  by  the  ferments  of 
specific  bacteria,  consequently  it  is  specific. 

As  Widal  concluded  years  ago,  agglutination  is  not  a  reaction  of 
immunity,  but  a  reaction  of  infection.  Both  agglutination  and  pre- 
cipitation are  evidences  of  parenteral  digestion. 


CHAPTER    XXVII 


OPSONINS 

Metschnikoff  ascribes  both  natural  and  acquired  immunity  to  the 
activity  of  the  phagocytes.  In  the  former  the  leukocytes  fall  on  the 
invading  bacteria  and  devour  them.  In  acquired  immunity  the  phago- 
cytes are  stimulated  by  the  attenuated  cultures,  or  vaccines,  and  learn 
how  to  cope  with  the  invaders.  The  phagocytes  constitute  the  mobile 
army  of  defense.  Without  previous  training  they  are  able  to  destroy 
certain  bacteria;  this  constitutes  natural  immunity.  By  first  bringing 
them  in  combat  with  attenuated  cultures,  which  they  satisfactorily  dis- 
pose of,  they  are  so  trained  that  they  become  able  successfully  to 
combat  virulent  forms ;  this  explains  acquired  immunity.  Both  depend 
on  the  efficiency  and  aggressiveness  of  the  phagocytes.  In  the  main, 
MetschnikofFs  facts  have  been  corroborated,  even  by  those  who  have 
desired  to  controvert  them.  Phagocytosis  is  more  marked  in  an 
immunized  animal  than  in  a  fresh  one  of  the  same  species.  Is  this 
due  to  increased  efficiency  on  the  part  of  the  phagocytes  or  to  impair- 
ment of  the  bacteria  ?  This  is  the  question  now  before  us. 

The  fundamental  facts  essential  to  the  solution  of  this  problem 
were  discovered  by  Denys  and  Leclef  in  1895.  They  showed  that 
phagocytes  can  be  obtained  and  mixed  with  bacteria  in  vitro  and  that 
phagocytosis  may  be  observed  under  conditions  controlled  by  the 
investigator.  They  established  the  following:  1.  Phagocytosis  pro- 
ceeds in  vitro  the  same  as  in  vivo.  2.  When  the  phagocytes  are  col- 
lected from  an  animal  immunized  and  from  one  not  immunized  and 
these  are  washed  free  from  all  serum  and  mixed  with  the  immunizing 
bacteria  suspended  in  either  salt  solution  or  normal  serum  there  is  no 
phagocytic  action  in  either  tube.  The  phagocytes  from  the  immunized 
animal  and  those  from  the  non-immunized  animal  are  alike  impotent. 
3.  When  the  two  kinds  of  phagocytes  are  mixed  with  the  bacteria  and 
suspended  in  the  serum  of  an  immunized  animal,  phagocytic  action 
begins  promptly  and  is  equally  marked  in  the  two  tubes. 


208  OPSONINS 

These  facts  show  that  the  agent  which  develops  and  stimulates 
phagocytosis  is  in  solution  in  the  blood  of  the  immunized  animal,  is 
not  present  in  the  blood  of  the  non-immunized  animal,  and  is  apart 
from  the  leukocytes. 

The  work  of  Denys  and  Leclef  seems  to  have  been  ignored  for 
some  years,  and  quite  ignorant  of  it,  Leishman  in  1902  showed  that 
phagocytic  action  can  be  demonstrated  in  a  drop  of  human  blood 
freshly  taken.  He  determined  the  degree  of  phagocytic  action  by 
counting  the  included  bacteria  in  a  number  of  phagocytes  and  showed 
that  these  were  greater  in  the  blood  of  one  vaccinated  with  staphylo- 
cocci  than  in  normal  man.  In  this  way,  Leishman  opened  the  way  for 
"vaccine  therapy,"  which  has  since  been  widely  employed.  Wright  and 
Douglas  developed  this  treatment  and  proposed  that  the  substances  in 
the  blood  which  favor  phagocytic  activity  should  be  designated 
"opsonins"  (from  the  Greek,  t<t><rwvfaf  meaning,  "I  prepare  the  food"). 
They  showed  that  the  opsonins  in  normal  blood  vary  in  narrow  limits 
and  that  they  are  greatly  increased  by  the  subcutaneous  injection  of 
dead  bacterial  cultures,  known  as  vaccines.  It  is  only  fair  to  state 
that  many  years  earlier  Wright  had  used  heated  typhoid  bacteria  in  vac- 
cination against  this  disease.  It  is  not  my  purpose  to  discuss  here 
either  the  methods  of  employment  or  the  value  of  bacterial  "vaccines." 

The  normal  blood  of  man  and  other  animals  contains  opsonins  or 
substances  which  favor  phagocytic  action  with  numerous  bacteria,  and 
these  are  increased  by  proper  vaccination.  When  the  normal  blood 
contains  no  opsonin  for  a  given  bacterium,  one  can  be  developed  by 
vaccination,  that  is,  by  repeated  parenteral  administration  of  that 
bacterium  either  in  numbers  too  small  to  endanger  life  or  attenuated 
or  killed  by  heat.  In  some  instances  the  bacterium  while  in  the  body 
forms  a  capsule.  This  is  strikingly  true  of  anthrax  and  plague  bacilli. 
The  apparent  purpose  of  this  is  self-protection.  Not  all  bacteria  which 
are  taken  into  phagocytes  are  killed.  However,  even  in  these  cases 
phagocytosis  is  protective  to  the  body.  When  bacteria  undergo  com- 
plete disruption  outside  a  phagocyte,  its  poisonous  content  is  set  free 
and  exerts  its  deleterious  effects.  The  inclusion  of  dead  bacteria  is 
protective  for  the  same  reason.  When  there  is  no  phagocytosis  and 
the  bacteria  are  rapidly  split  up  by  a  bactericidal  serum,  the  greater 


OPSONINS  209 

is  the  danger  to  life.  It  follows  from  this  that  a  large  opsonin  blood 
content  is  more  protective  than  a  powerful  bactericidal  blood. 

Certain  bacteria  are  readily  devoured  by  phagocytes  in  normal 
salt  solution  or  in  inactivated  normal  serum.  In  other  words,  with 
these  bacteria  opsonins  are  not  essential  to  phagocytosis.  Naturally 
these  are  avirulent  organisms.  It  must  not  be  inferred,  however,  that 
all  avirulent  bacteria  are  phagocitized  without  the  aid  of  opsonins.  The 
phagocytic-favoring  substances  are  of  two  kinds.  The  first,  known  as 
tropins,  are  evidently  of  relatively  simple  structure,  are  not  inactivated 
by  heat,  and  consequently  are  present  in  heated  serum.  The  true 
opsonins  are  more  complicated,  consisting  of  a  thermolabile  part,  known 
as  alexin  or  complement,  and  a  thermostabile  part,  known  as  fixator 
or  amboceptor.  Since  both  parts  are  essential  to  complete  action, 
serum  is  inactivated  by  heat.  Neither  tropins  or  opsonins  induce  recog- 
nizable alterations  in  the  bacteria  which  they  prepare  for  phagocyto- 
sis. In  the  study  of  phagocytosis  in  vitro,  MetschnikofFs  finding  that 
bacteria  are  devoured  by  the  polynuclear  leukocytes  has  been  confirmed. 
The  large  mononuclear  cells  are  not  wholly  indifferent  in  the  disposal 
of  bacteria  but  in  this  they  play  a  very  subordinate  role.  On  the 
other  hand,  the  macrophages  are  the  chief  consumers  of  animal  cells, 
such  as  red  corpuscles,  spermatozoa,  etc. 

It  was  shown  early  in  these  studies  that  dead,  highly  virulent  bac- 
teria are  not  readily  taken  up  by  leukocytes  except  in  the  presence  of 
immune  serum.  This  indicates  that  dead,  as  well  as  living  bacteria, 
especially  if  of  virulent  strains,  are  prepared  by  the  opsonins  as  food 
for  the  leukocytes.  From  this  we  infer  that  in  whatever  reaction  there 
may  be  between  the  opsonins  and  the  bacterial  cells,  the  later  show 
no  vital  activity. 

It  was  shown  by  Neufeld  and  Handel  that  when  rabbits  have  been 
treated  with  injections  of  milk  or  egg  white,  their  serum  causes  leu- 
kocytes to  engulf  milk  globules  and  albumin  emulsified  with  oil.  The 
engulfment  is  not  due  to  the  oil  but  to  the  casein  or  albuminous 
envelopes. 

It  is  well  to  show  that  the  opsonins  do  not  act  by  stimulating  the 
leukocytes.  When  leukocytes  are  kept  in  contact  with  immune  serum 
for  twenty  minutes  at  37  C,  then  removed  and  washed  wholly  free 
from  the  serum  and  then  brought  into  contact  with  the  bacteria  there 


210  OPSONINS 

is  no  phagocytosis.  On  the  other  hand,  when  the  bacteria  are  kept 
in  contact  with  the  immune  serum,  then  washed  and  brought  in 
contact  with  the  leukocytes,  active  phagocytosis  begins.  This  shows 
that  the  serum  of  an  animal  immunized  to  a  streptococcus,  for  instance, 
does  not  stimulate  the  leukocytes  but  in  some  way  makes  the  strepto- 
cocci more  inviting  as  a  food. 

Parenthetically  it  should  be  stated  that  there  are  substances  which 
stimulate  phagocytes,  such  as  nuclein,  peptone,  quinin,  potassium 
iodid,  etc.,  but  these  have  nothing  to  do  with  opsonins.  Anesthetics 
inhibit  phagocytic  action  and  the  same  is  true  of  narcotics. 

The  study  of  phagocytosis  in  vitro  has  shown  that  the  immune 
serum  and  the  leukocytes  need  not  come  from  the  same  animal,  not 
even  from  the  same  species.  Hektoen  has  shown  that  immune  sera 
from  horses,  dogs,  rabbits,  guinea-pigs,  etc.,  prepare  streptococci  so 
that  they  are  readily  devoured  by  leukocytes  from  man.  This  list  of 
animals  has  been  extended  by  Hektoen's  students  so  that  it  includes 
certain  cold-blooded  ones.  Streptococci  sensitized  with  immune  sera 
from  warm-blooded  animals  are  readily  devoured  by  phagocytes  from 
cold-blooded  ones.  This  makes  it  all  the  more  certain  that  the  reaction 
is  between  the  serum  and  the  bacteria.  When  the  latter  are  prepared 
by  the  former,  a  phagocyte  from  any  kind  of  an  animal  will  eat  them. 

The  opsonins  do  not  kill  the  bacteria;  indeed,  they  do  not  stop 
their  growth  nor  lessen  their  virulence.  When  bacteria  have  been  in 
contact  with  homologous  immune  sera  long  enough  to  be  sensitized 
and  are  then  placed  in  ordinary  culture  media,  they  multiply,  and 
their  progeny  are  not  found  to  be  sensitized.  We  infer  that  the  union 
between  cell  substance  and  opsonin  has  no  destructive  or  radical  effect 
on  the  former.  In  fact,  Hektoen  has  shown  that  anthrax  bacilli,  strep- 
tococci and  pneumococci  grow  abundantly  in  homologous  immune 
sera. 

Phagocytosis  proceeds  in  the  same  way  in  vitro  and  vivo.  The 
serum  from  a  rabbit  immunized  to  streptococcus,  will  sensitize  the 
streptococcus  in  a  test-tube  or  in  the  abdominal  cavity  of  a  guinea- 
pig,  and  a  healthy  phagocyte  from  any  source  will  eat  the  prepared 
food  in  either  place.  Indeed  many  bacteria  are  more  readily  disposed 
of  by  the  phagocytes  in  test-tubes  than  in  the  body,  because  in  the 
latter  they  develop  in  the  second  and  subsequent  generations,  protec- 


OPSONINS  211 

tive  capsules.  Some  show  other  alterations  which  evidently  have  the 
same  purpose.  We  distinguish  between  "animal"  and  "culture"  bac- 
teria inasmuch  as  the  former  are  more  resistant  especially  to  the 
destructive  secretions  of  the  body  cells. 

Observation  shows  that  most  of  the  bacteria  taken  into  the  leuko- 
cytes are  completely  digested.  The  bacterial  cells  become  pale,  then 
granular,  and  finally  disappear  altogether.  Occasionally  a  phagocyte 
takes  in  more  bacteria  than  it  can  digest  and  injures  itself,  in  some 
cases,  fatally.  The  digestive  phenomena  are  identical  in  the  test-tube 
and  in  the  body.  The  tubercle  bacillus,  although  readily  engulfed  by 
phagocytes,  is  not  digested.  These  bacilli  probably  owe  their  protec- 
tion to  the  abundant  deposits  of  wax  and  fat  which  they  contain.  The 
intracellular  ferment  of  the  phagocytes  is  studied  by  collecting  a  large 
number  of  leukocytes  and  dissolving  them  in  very  dilute  acid  or  alkali 
or  breaking  them  down  by  alternating  freezing  and  thawing. .  This 
ferment  is  not  destroyed  by  a  temperature  of  65  C.  It  is  able  to 
digest  many  bacteria,  such  as  streptococci  and  pneumococci,  which  are 
not  affected  by  extracellular  ferments.  Levaditi  found  that  the  intra- 
cellular ferment  of  the  polynuclear  cells  acts  on  bacteria  but  is  with- 
out effect  on  red  corpuscles,  trypanosomes  and  spirochetes,  while  that 
of  the  large  mononuclear  cells  acts  on  the  latter  group  and  has  but 
little  or  no  action  on  bacteria.  Opie  found  the  ferment  from  the  poly- 
nuclear  cells,  which  he  calls  leukoprotease,  acts  in  neutral  or  feebly 
alkaline  solution,  while  that  from  the  large  mononuclear  cells,  which 
he  calls  lymphoprotease,  acts  only  in  acid  solution.  When  leukopro- 
tease is  set  free  in  the  body  by  the  disruption  of  the  polynuclear  leuko- 
cytes, its  action  is  inhibited  by  soluble  substances  in  the  plasma.  When 
lymphoprotease  is  set  free  in  the  blood,  its  action  is  inhibited  by  the 
alkalinity  of  the  fluid.  It  appears  from  this  that,  physiologically,  both 
of  these  ferments  are  active  only  within  the  cells  which  elaborate  them. 
It  is  by  virtue  of  these  intracellular  ferments  that  the  phagocytes  kill 
and  digest  the  bacterial  and  other  cells  which  they  engulf. 

Whether  the  action  of  opsonins  on  bacteria  is  wholly  physical, 
wholly  chemical,  or  both,  we  do  not  know.  Neufeld  states  that  this 
action  is  not  chemotaxic,  because  unsensitized  bacteria,  in  suspension 
with  phagocytes,  collect  about  the  latter  quite  as  plainly  as  sensitized 
bacteria  do;  but  with  the  former  there  is  no  phagocytosis.  It  seems 


212  OPSONINS 

justifiable  with  our  present  knowledge  to  conclude  that  the  opsonins  rob 
the  bacteria  of  some  defensive  weapon  and  thus  make  them  easy  prey 
for  the  phagocytes.  To  go  farther  than  this  at  present  would  result  in 
unprofitable  speculation. 


CHAPTER    XXVIII 


GERMICIDAL    SERA 

Normal  Sera. — As  early  as  1872  Lewis  and  Cunningham  demon- 
strated the  fact  that  bacteria  injected  into  the  circulation  rapidly  dis- 
appear. In  the  blood  of  twelve  animals  which  had  been  given  such  injec- 
tions, bacteria  could  be  found  after  six  hours  in  only  seven.  In  a 
second  series  of  thirty,  bacteria  were  found  after  twenty-four  hours 
in  the  blood  of  only  fourteen,  and  in  a  third  experiment  with  seven- 
teen animals,  bacteria  were  found  in  only  two  when  the  examination 
was  made  within  from  two  to  seven  days. 

In  1874,  Traube  and  Gscheidlen  found  that  arterial  blood  taken, 
under  aseptic  precautions,  from  the  jugular  vein  of  rabbits  into  which 
a  small  amount  of  a  putrifying  fluid  had  been  injected  forty-eight 
hours  previously,  failed  to  undergo  decomposition  for  months.  They 
attributed  the  germicidal  properties  of  blood  to  the  ozonized  oxygen. 
Grohmann  found  that  anthrax  bacilli  decrease  in  virulence  on  being 
kept  in  plasma. 

In  1887,  Fodor  found  that  anthrax  bacilli  rapidly  decrease  in 
numbers  when  injected  into  the  circulation.  He  then  took  blood  from 
the  heart  with  a  sterile  pipette,  inoculated  it  with  anthrax,  kept  it  at 
incubator  temperature  and  plated  it  out  at  intervals.  He  found  that 
the  number  decreased  for  some  hours  and  then  multiplied  abundantly. 

In  1888  Nuttall  found  that  defibrinated  blood  from  various  species 
of  animals,  sheep,  rabbits,  mice  and  pigeons,  destroys  both  pathogenic 
and  non-pathogenic  bacteria.  He  also  confirmed  the  finding  of  Fodor 
that  after  a  time  the  blood  loses  its  germicidal  action  and  becomes  a 
suitable  culture-medium  in  which  the  bacteria  multiply  abundantly.  In 
his  studies,  Nissen  reached  the  following  conclusions:  1.  The  addition 
of  small  quantities  of  salt  solution  or  bouillon  to  the  blood  does  not 
destroy  its  germicidal  properties.  2.  Cholera  and  typhoid  bacilli  are 
easily  destroyed  by  fresh  blood.  3.  In  a  given  volume  of  blood  there  is 
a  maximum  number  of  bacilli,  which  can  be  destroyed.  4.  Blood,  the 
coagulability  of  which  has  been  destroyed  by  the  injection  of  peptone, 


214  GERMICIDAL    SERA 

is  still  germicidal.  5.  Blood  in  which  coagulation  is  prevented  by 
the  addition  of  25  per  cent,  of  magnesium  sulphate,  has  its  germicidal 
properties  decreased.  6.  Filtered  blood  plasma  from  the  horse  is 
germicidal. 

At  one  time,  Behring  attributed  the  action  of  the  blood  of  the 
white  rat  on  anthrax  bacilli  to  its  alkalinity.  He  made  titrations  which 
showed  that  the  blood  serum  of  the  rat  is  more  alkaline  than  that  of 
certain  susceptible  animals,  as  the  cow,  rabbit  and  guinea-pig.  How- 
ever, there  are  other  and  more  important  points  in  which  these  animals 
differ  from  the  rat  than  in  slightly  less  blood  alkalinity.  Had  he  shown 
that  the  blood  of  the  adult  rat,  which  is  highly  resistant  to  anthrax,  is 
more  alkaline  than  that  of  the  young  rat,  which  is  more  susceptible, 
his  argument  would  have  been  more  reasonable;  but  even  then  it 
would  not  be  convincing  evidence. 

In  1890,  Buchner  made  valuable  contributions  to  our  knowledge 
of  the  germicidal  properties  of  blood  and  stated  his  conclusions  as  fol- 
lows :  1.  The  germicidal  action  of  blood  serum  is  not  due  to  phagocytes, 
because  it  is  not  influenced  by  the  alternate  freezing  and  thawing  of 
the  blood,  by  which  the  leukocytes  are  destroyed.  2.  The  germicidal 
properties  of  the  cell-free  serum  must  be  due  to  its  soluble  constituents. 
3.  Neither  neutralization  of  the  serum,  nor  the  addition  of  pepsin,  nor 
the  removal  of  carbon  dioxid  gas,  nor  treatment  with  oxygen,  has  any 
effect  on  the  germicidal  properties  of  the  blood.  4.  Dialysis  of  the 
serum  against  water  destroys  its  activity,  while  dialysis  against  0.75 
per  cent,  salt  solution  does  not.  In  the  diffusate  there  is  no  germicidal 
substance.  The  loss  by  dialysis  with  water  must  be  due  to  the  with- 
drawal of  the  inorganic  salts  of  the  serum.  5.  The  same  is  shown  to  be 
the  case  when  the  serum  is  diluted  with  water  and  when  it  is  diluted 
with  salt  solution ;  in  the  former  instance  the  germicidal  action  is 
destroyed  while  in  the  latter  it  is  not.  6.  The  inorganic  salts  have  in 
and  of  themselves  no  germicidal  action.  They  are  active  only  in  so 
far  as  they  affect  the  normal  properties  of  the  albuminates  of  the 
serum.  The  germicidal  properties  of  the  serum  reside  in  its  albumin 
constituents.  7.  The  difference  in  the  effects  of  active  serum  and 
that  which  has  been  heated  to  55  C.  is  due  to  the  altered  condition  of 
the  albuminate.  The  difference  may  possibly  be  a  chemical  one  (due 
to  changes  within  the  molecule)  or  it  may  be  due  to  alterations  in 


GERMICIDAL    SERA  215 

mycelial  structure.  The  albuminous  bodies  act  on  the  bacteria  only 
when  the  former  are  in  an  active  state. 

Vaughan  pointed  out  an  inconsistency  between  Buchner's  experi- 
mental results  and  his  conclusions.  Experimentally  he  ascertained  that 
peptic  digestion  of  blood  serum  does  not  destroy  its  germicidal  proper- 
ties and  yet  he  concludes  that  the  active  principle  is  serum  albumin. 
Since  serum  albumin  is  converted  into  peptone  by  peptic  digestion  and 
since  peptone  forms  an  excellent  medium  for  bacterial  growth,  Buch- 
ner's conclusion  that  serum  albumin  is  the  germicidal  constituent  of 
blood  serum  cannot  be  true.  This  criticism  has  held. 

In  1893  Vaughan  and  McClintock,  after  reviewing  the  literature 
up  to  that  time,  reported  their  work  on  the  germicidal  constituents  of 
blood  serum  as  follows:  1.  Serum  albumin  is  not  the  germicidal  con- 
stituent. 2.  The  germicidal  substance  must  belong  to  the  proteins. 
Otherwise,  it  would  be  difficult  to  explain  the  fact  that  a  temperature 
of  85  C.  renders  blood  serum  inactive.  3.  The  only  protein  likely  to 
be  present  in  blood  and  which  is  not  destroyed  by  peptic  digestion  is 
nuclein. 

Having  reached  these  conclusions,  the  following  questions  naturally 
presented:  1.  Is  there  a  nuclein  in  blood  serum?  2.  Has  this  nuclein, 
if  there  be  any,  germicidal  properties?  Their  work  answered  both 
these  questions  in  the  affirmative.  The  existence  of  nuclein  in  blood 
serum  was  confirmed  by  Lilienfeld  and  by  Kossel,  and  its  germicidal 
action  by  the  latter.  Furthermore,  it  was  demonstrated  that  injec- 
tions of  nucleinic  acid,  prepared  from  yeast  and  spleen  cells,  increased 
both  the  number  of  leukocytes  in  the  blood  and  the  germicidal  action 
of  the  serum.  However,  Buchner  very  properly  declined  to  accept 
nucleinic  acid  as  the  chief  germicidal  constituent  of  serum,  since  the 
latter  is  inactivated  at  from  56  to  58  C.,  while  aqueous  solutions  of 
nucleinic  acid  are  not  altered  by  much  higher  temperatures. 

It  should  be  stated,  parenthetically,  that  the  relation  of  nucleinic 
acid  to  the  intracellular  ferment  of  the  polynuclear  leukocytes  has 
never  been  satisfactorily  worked  out.  The  researches  of  Schattenfroth 
and  others  have  shown  marked  differences  between  the  extracellular 
and  intracellular  constituents  of  the  blood.  The  latter  has  no  hemo- 
lytic  action  on  the  red  corpuscles  of  other  species  while  the  former 
may  have.  The  intracellular  germicide  is  not  affected  by  the  salt 


216  GERMICIDAL    SERA 

content  of  the  medium,  while  the  extracellular  substance  is  inactivated 
by  the  removal  of  salt  from  the  serum  by  dialysis.  Daubler  came  to 
the  conclusion  that  the  germicidal  constituent  of  the  serum  and  that  of 
the  leukocytes  are  not  identical,  the  latter  remaining  active  after  being 
heated  to  60  C.  He  also  found  that  the  germicidal  substances 
obtained  from  the  leukocytes  of  different  species  differ  in  measurable 
degree  when  tested  on  the  same  bacteria.  Many  other  investigators 
produced  evidence  of  the  fact  that  the  intracellular  and  extracellular 
germicidal  constituents  are  not  identical. 

Petterson  designates  the  intracellular  bactericidal  constituents  of 
leukocytes  and  other  cells  as  "endolysis"  and  his  pupil,  Kling,  sum- 
marizes our  knowledge  on  this  subject  as  follows:  1.  The  germicidal 
substances  (endolysins)  of  the  polynuclear  leukocytes  may  be  obtained 
by  the  following  methods  (a)  By  digesting  the  cells  for  half  an  hour 
at  50  C.  in  bouillon;  (b)  by  extracting  the  cells  with  weak  acid  or 
alkali;  (c)  by  alternate  freezing  and  thawing  of  the  cells.  They 
cannot  be  obtained  by  digesting  with  bouillon  at  37  C.,  nor  with  salt 
solution,  nor  with  5  per  cent,  inactivated  serum.  2.  As  tested  on 
Bacillus  subtilis,  the  endolysin  bears  a  temperature  of  65  C.  without 
recognizable  effect  on  its  germicidal  action,  and  it  is  not  until  the 
temperature  is  increased  to  75  C.  that  any  such  effect  is  noticed.  The 
endolysins  can  in  daylight  at  room  temperature,  and  in  the  dark  at  37 
C.,-  be  evaporated  to  dryness,  and  in  this  state  they  may  be  heated  for 
half  an  hour  at  100  C.  without  being  destroyed.  The  serum  germi- 
cides may  be  obtained  in  the  dry  state  in  the  same  manner,  but  when 
heated  to  this  temperature  they  are  inactivated.  The  endolysis,  as 
tested  on  the  subtilis,  does  not  pass  through  a  Pukall  filter,  while  the 
serum  germicide  does.  The  endolysins,  as  tested  on  the  subtilis,  the 
anthrax  and  the  typhoid  bacillus  are  destroyed  by  the  Roentgen  ray, 
while  the  serum  germicide  is  not.  The  endolysins  can  be  extracted 
with  ether,  while  the  serum  lysins  are  destroyed  by  ether.  3.  The 
activity  of  an  inactivated  extract  of  the  leukocytes  of  the  rabbit,  as 
tested  on  the  subtilis,  may  be  restored  by  the  addition  of  a  small 
quantity  of  the  serum  extract  in  a  fresh  state.  Likewise,  an  inacti- 
vated normal  serum  of  the  rabbit  or  the  inactive  serum  of  the  guinea- 
pig  may  be  complemented  by  the  addition  of  a  small  amount  of  the 
leukocytic  extract  from  the  rabbit  or  guinea-pig,  respectively.  Fur- 


GERMICIDAL    SERA  217 

thermore,  an  inactivated  leukocytic  extract  from  a  guinea-pig  can 
be  activated  by  the  addition  of  a  small  amount  of  the  normal  serum 
of  a  rabbit.  4.  Extracts  from  the  polynuclear  leukocytes  of  rabbits, 
guinea-pigs,  and  cats  destroy  in  vitro  the  timothy,  grass  and  butter 
bacilli.  The  extracts  from  rabbits'  leukocytes  have  a  bactericidal  action 
on  the  bacillus  tuberculosis  of  man.  Extracts  of  rabbit,  guinea-pig 
and  cat  macrophages  (mononuclear  cells)  do  not  destroy  these  acid- 
fast  bacilli  in  vitro.  The  same  is  true  of  the  extracts  from  the  thymus 
glands  of  rabbits.  Living  polynuclear  leukocytes  injected  into  guinea- 
pigs  decrease  the  virulence  of  the  bacillus  tuberculosis  of  man.  The 
leukocytes  of  the  guinea-pig  do  not  have  this  effect.  This  must 
suffice  to  show  that  the  intracellular  and  extracellular  germicidal  con- 
stituents of  the  blood  are  not  the  same  and  we  will  now  return  to  a 
consideration  of  the  germicidal  action  of  blood  serum. 

Buchner  named  the  germicidal  constituents  of  serum,  "alexins" 
(defenders).  These  are  inactivated  at  from  56  to  58  C.  At  first  he 
believed  alexins  to  be  protein  bodies,  but  later  he  regarded  them  as 
proteolytic  ferments  or  enzymes.  He  did  not  succeed  in  isolating  the 
alexins,  but  he  believed  that  they  are  secretions  of  the  polynuclear 
leukocytes  and  he  proposed  that  these  should  be  designated  "alexo- 
cytes,"  which,  however,  has  not  been  adopted.  Metschnikoff  holds 
that  the  alexins  from  the  polynuclear  cells  (microphages)  are  bac- 
tericidal, while  those  from  the  large  mononuclear  cells  (macrophages) 
destroy  red  corpuscles  and  other  animal  cells.  He  designates  all 
alexins  as  cytases  and  divides  these  according  to  the  cells  supposed 
to  secrete  them  into  microcytases  and  macrocytases.  However,  it 
has  not  been  demonstrated  that  the  production  of  alexins  is  limited 
to  the  leukocytes,  both  mononuclear  and  polynuclear.  Furthermore, 
Metschnikoff  did  believe  that  alexins  are  intracellular  ferments  and 
that  their  presence  in  blood  serum  is  due  to  the  dissolution  of  the 
leukocytes  and  that  there  are  no  free  alexins  in  blood  plasma,  except 
possibly  a  trace  due  to  the  physiologic  dissolution  of  the  leukocytes. 
As  has  been  seen,  this  view  is  no  longer  tenable. 

It  was  shown  by  the  work  of  Metschnikoff  and  Bordet  that  a 
germicidal  serum  which  has  been  inactivated  by  heating  to  from  56 
to  58  C.  may  be  reactivated  on  the  addition  of  fresh  serum.  Further 
work  has  shown  that  the  bacteriolytic  substances,  present  in  both  nor- 


218  GERMICIDAL    SERA 

mal  and  immune  sera  consists  of  two  parts,  one  of  which  is  ther- 
molabile  and  the  other  is  thermostabile.  This  is  probably  true  of  most, 
if  not  all,  enzymes.  The  thermolabile  part  is  now  known  as  alexin 
or  complement;  the  thermostabile  part  is  known  as  fixator,  sensi- 
tizer  or  amboceptor.  The  former  is  present  in  all  sera  and  the 
weight  of  evidence  is  that  it  is  non-specific.  The  amboceptor  is  the 
specific  part.  According  to  Ehrlich's  theory  the  amboceptor,  which 
he  has,  at  different  times,  designated  as  intermediary  and  immune  body, 
but  which  is  now  generally  known  as  amboceptor,  combines  on  the  one 
hand  with  the  bacterial  or  other  cell  and  on  the  other  with  the  com- 
plement. The  union  between  the  amboceptor  and  cell  may  take  place 
at  low  temperature  (even  at  0  C,  32  F.),  but  the  complement  enters 
into  the  reaction  only  at  temperatures  not  far  above  or  below  that  of 
the  animal  body.  The  complement  is  destroyed  by  a  temperature  of 
from  56  to  58  C.,  but  the  amboceptor  is  not  injured  at  this  temperature. 
When  a  serum  is  heated  to  this  temperature  it  is  inactivated;  its  bac- 
teriolytic  or  cytolytic  action  is  interrupted  because  the  complement  is 
destroyed,  but  the  ambocepter  is  not  impaired  and  the  serum  is  reacti- 
vated by  the  addition  of  fresh  complement  which  exists  in  both  normal 
and  immune,  unheated  serum.  This  applies  to  all  cytolytic  sera, 
whether  they  manifest  their  activity  on  bacteria,  red  blood  cells,  sper- 
matic cells  or  other  kind  of  cell.  According  to  Ehrlich's  teachings  the 
union  of  amboceptor  with  cell  on  one  hand  and  with  the  complement 
by  the  other  is  chemical,  while  Bordet  believes  the  amboceptor,  which 
he  calls  a  sensitizer,  acts  as  a  mordant  in  coloring  and  the  complement 
may  be  regarded  as  a  dye.  In  other  words,  Bordet's  explanation 
supposes  the  action  of  physical  rather  than  chemical  forces. 

To  conclude  this  part  of  our  subject,  we  may  say  that  normal  blood, 
and  the  serum  obtained  from  it,  contains  non-specific  bactericidal  fer- 
ments or  enzymes.  These  vary  in  amount,  kind  and  efficiency  in 
different  species.  In  a  general  way,  the  blood  is  a  germicidal  fluid  and 
it  owes  this  function  to  the  presence  of  proteolytic  enzymes.  In  normal 
blood  these  enzymes  are  not  specific  and  they  display  marked,  destruc- 
tive action  on  certain  bacteria,  and  are  wholly  without  effect  on 
others.  Living  cholera  cultures,  in  doses  that  might  infect  by  way 
of  the  intestines,  can  be  injected  into  man  subcutaneously  or  intra- 
venously without  ill  effect.  Cattle  bear  large  injections  of  the  organ- 


GERMICIDAL    SERA  219 

isms  of  symptomatic  anthrax  provided  all  goes  into  the  blood  current 
directly  and  the  subcutaneous  tissue  is  not  infected. 

Immune  Sera. — The  words,  immune  sera,  are  likely  to  be  mis- 
leading in  this  connection.  Immunity  due  to  bactericidal  constitu- 
ents of  the  blood,  whether  it  be  natural  or  acquired,  is  always  rela- 
tive. Even  the  immunity  secured  by  one  attack  of  the  disease  may  be 
overcome,  in  most  instances  at  least,  by  the  administration  of  an  over- 
whelming dose  of  the  virus  in  virulent  form.  The  man  who  has 
once  had  smallpox  may  have  it  again  when  brought  into  intimate 
and  long-continued  contact  with  the  virus.  The  immunity  induced 
by  one  attack  of  yellow  fever  is  probably  the  most  complete  and  per- 
sistent form  known  among  the  diseases  to  which  man  is  susceptible. 
The  only  way  in  which  a  man  who  has  had  this  disease  may  be  exposed 
again  is  through  the  bite  of  an  infected  mosquito,  and  the  virus  intro- 
duced in  this  way  is  always  limited  and  fairly  constant  in  amount. 
We  do  not  know  what  would  happen  to  a  yellow  fever  immune  should 
100  or  1,000  infected  mosquitos  bite  him  in  the  same  hour.  Experi- 
mentally the  injection  of  a  large  number  of  bacteria  into  the  peritoneal 
cavity  of  highly  immune  animals  kills  quickly,  and  the  more  marked 
the  immunity,  provided  it  be  due  to  germicidal  substances  in  the  blood 
and  lymph,  the  more  promptly  and  more  certainly  does  it  kill.  The 
explanation  of  this  fact  is  that  the  fluids  of  the  body  promptly  split 
up  the  bacterial  cells,  setting  the  protein  poison  free  in  large  amount. 
Nothing  exactly  similar  to  this  occurs  in  nature,  but  the  experiment 
is  of  great  value  in  demonstrating  the  phenomena  of  bacteriolysis. 
A  highly  germicidal  blood  is  of  great  value  in  preventing  infection, 
because  the  first  few  organisms  that  find  their  way  into  the  body  are 
promptly  killed  before  they  can  multiply  and  while  the  amount  of 
poison  set  free  is  too  small  to  produce  any  marked  effect.  On  the 
other  hand,  it  would  be  highly  disastrous  for  the  blood  to  become  sud- 
denly and  highly  germicidal  when  the  body  is  filled  with  bacteria.  This 
would  mean  sure  and  speedy  death.  Phagocytes  not  only  serve  the 
body  in  feeding  on  bacteria,  but  they  protect  the  body  from  the  poison 
which  results  from  the  extracellular  cleavage  of  the  bacteria. 

The  essential  difference  between  the  germicidal  constituent  of  nor- 
mal serum  and  that  of  immune  serum  is  that  the  latter  is  specific 


220  GERMICIDAL    SERA 

while  the  former  is  not.  Whether  the  general  enzyme  is  so  changed 
as  to  have  specific  action  or  a  wholly  new  enzyme  has  been  developed, 
no  one  can  say  with  certainty.  Pfeiffer  found  that  when  a  mixed 
culture  of  the  vibrio  of  cholera  and  another  vibrio  was  injected  into 
the  peritoneal  cavity  of  a  guinea-pig  immunized  to  cholera,  all  the 
cholera  vibrios  were  dissolved  and  all  the  others  were  left  whole. 
When  the  same  mixed  culture  was  injected  into  the  abdomen  of  a 
guinea-pig  immunized  with  the  Nordhafen  vibrio,  all  these  were  dis- 
solved and  the  cholera  vibrios  left  unharmed.  The  great  majority 
of  bacteria  are  harmless  because  they  are  speedily  destroyed  by  the 
digestive  secretions  of  the  animal  body.  The  germicidal  constituent 
of  man's  blood  is  easily  made  specific  by  vaccination  with  cholera 
or  typhoid  bacilli.  So  far  no  specific  bacteriolytic  substance  has  been 
developed  in  the  blood  of  any  animal  with  anthrax  bacilli  or  strepto- 
cocci. It  is  true  that  Pasteur  developed  highly  efficient  vaccines  against 
anthrax,  but  these  increase  phagocytic  activity,  probably  through  the 
formation  of  opsonins,  and  do  not  develop  immune  sera.  It  will 
be  understood  that  we  are  not  now  concerned  with  toxin  immunity. 
We  are  confining  ourselves  to  the  study  of  specific  bacteriolysins. 

It  has  been  positively  shown  that  the  proteolytic  enzyme  which 
destroys  the  bacteria  is  not  an  albuminous  substance.  Pfeiffer  and 
Proskauer  precipitated  a  highly  active  cholera  serum  with  alcohol 
and  allowed  it  to  stand  for  three  months  with  frequent  change  of 
the  alcohol.  From  the  hard  mass  which  formed,  they  extracted  with 
distilled  water  a  highly  active  body  which  responded  to  none  of  the 
protein  reactions.  Some  serum  preserved  by  the  addition  of  0.5  per 
cent,  phenol  stood  for  ten  years  in  Pfeiffer's  laboratory  and  was  found 
to  be  active  at  the  end  of  that  time.  The  enzyme  is  not  always  so 
susceptible  to  heat  as  was  first  supposed  and  some  samples  at  least 
require  a  temperature  of  70  C.  for  one  hour  for  complete  inactivation. 

When  a  highly  immune  serum  is  injected  into  an  animal  it  increases 
its  resistance  to  its  homologous  bacterium.  Animals  are  actively 
immunized  by  repeated  treatments  with  the  bacteria,  either  in  attenu- 
ated form  or  in  small  doses  of  the  virulent  form.  Animals  thus  actively 
immunized  furnish  an  immune  serum  with  which  other  animals  may 
be  passively  immunized.  It  is  generally  believed  that  living  bacteria 
give  a  better  active  immunization  than  dead  cultures.  Many  years 


GERMICIDAL    SERA  221 

ago  Feran  used  living  cholera  bacilli  subcutaneously  as  a  vaccine  against 
this  disease.  Wright  introduced  typhoid  vaccination  with  heated  cul- 
tures and  this  has  proved  highly  successful  and  is  now  widely  used, 
not  only  among  soldiers  but  among  civilians.  Strong  recommends 
highly  attenuated  typhoid  cultures.  Besredka  combines  active  and 
passive  immunity  in  vaccination  against  typhoid.  The  growth  from 
a  forty-eight  hour  agar-culture  is  mixed  with  a  small  amount  of 
salt  solution.  To  this  is  added  a  homologous  immune  serum  and  the 
mixture  allowed  to  stand  for  twelve  hours.  This  results  in  agglutina- 
tion. The  bacteria  are  washed  in  salt  solution,  heated  to  56  C.  for  one 
hour  and  then  injected.  Vaccines  thus  prepared  cause  no  inflamma- 
tion. The  bacteria  are  sensitized  or  combined  with  the  amboceptor 
in  the  immune  serum  and  probably  are  more  easily  split  up  when 
introduced  into  the  body.  Dead  and  avirulent  plague  bacilli  have 
been  employed  as  a  vaccine  against  this  disease.  The  serum  of  men 
and  animals  actively  immunized  shows  a  higher  bacteriolytic  titer  than 
normal  serum,  but  we  are  not  sure  that  the  increased  resistance  is 
due  solely  to  this.  It  must  be  evident  that  this  method  of  securing 
increased  resistance  to  a  given  infection  is  in  principle  the  same  as 
that  secured  by  a  light  attack  of  the  disease.  The  body  cells  learn  how 
to  combat  the  infection.  They  learn  how  to  elaborate  a  specific  enzyme 
which  will  destroy  the  specific  bacteria  if  they  should  subsequently  find 
their  way  into  the  body.  For  instance,  the  blood  of  a  man  contains  no 
specific  enzyme  capable  of  destroying  the  cholera  bacillus.  A  small 
amount  of  this  organism  is  injected  under  his  skin,  and  the  cells  of  his 
body  under  this  new  irritant  learn  how  to  elaborate  a  specific  enzyme 
which  destroys  the  cholera  bacillus.  Later,  if  he  drinks  water  contain- 
ing this  organism,  it  must  be  plain  that  he  has  a  distinct  advantage  over 
the  unvaccinated  man  in  resisting  the  infection.  The  world  is  indebted 
to  the  Spanish  physician,  Feran,  who  first  had  the  intelligence  and 
courage  to  employ  this  method  in  combating  cholera.  He  was  wiser 
than  his  time  and  from  his  work  has  come  vaccination  against  typhoid 
and  plague  in  man. 

PfeifTer  and  Mark  have  endeavored  to  ascertain  in  what  part  of 
the  body  this  specific  immunizing  enzyme  is  formed.  For  this  purpose 
they  inoculated  rabbits  and  killing  one  from  time  to  time  tested 
extracts  from  the  various  organs.  They  found  that  the  bacteriolytic 


222  GERMICIDAL    SERA 

enzyme  appears  in  the  spleen  first,  and  within  twenty-four  hours  after 
the  inoculation.  The  bacteriolytic  titer  of  the  spleen  extract  increased 
before  that  of  the  circulating  blood.  However,  it  must  not  be  inferred 
that  the  spleen  is  the  only  organ  in  which  the  specific  enzyme  is 
formed.  It  is  possible  that  many  of  the  cells  of  the  body  are  capable 
of  performing  this  function  and  that  an  organ  specially  active  in 
resisting  one  infection  may  play  a  subordinate  role  in  another.  Heck 
made  a  comparative  study  of  the  persistence  of  the  typhoid  bacilli  in 
various  organs  of  normal  and  immunized  animals  after  intravenous 
injections.  In  the  normal  animals,  they  were  not  found  in  the  circu- 
lating blood  after  six  hours;  were  present  in  the  kidneys  and  lungs 
up  to  the  third  day;  in  the  liver  after  the  fifth  day;  in  the  spleen 
after  the  twentieth  day  and  in  the  bone  marrow  up  to  the  sixtieth 
day.  In  immunized  animals,  they  disappeared  first  from  the  spleen 
and  bone  marrow,  and  all  organs  were  sterile  on  the  third  day. 

The  constitution  of  the  specific  bacteriolysins  is  similar  to  that  of 
the  non-specific  in  normal  blood.  They  consist  of  alexin  or  complement 
and  fixator  or  amboceptor.  Their  specificity  lies  in  the  amboceptor 
and  it  is  this  which  combines  with,  or  acts  on,  the  bacterial  cells. 
PfeifTer  describes  the  action  of  a  highly  immune  serum  on  its  homol- 
ogous bacterium  as  follows :  "The  micro-organisms  first  lose  their 
motion,  then  swell  and  finally  contract  into  balls,  in  which  some  motion 
may  be  still  seen,  showing  that  living  bacilli  are  being  dissolved.  For 
a  time  the  granules  seem  like  micrococci  and  can  be  stained.  They 
gradually  grow  smaller  and  smaller  and  finally  dissolve  in  the  fluid 
just  as  sugar  or  salt  dissolves  in  water." 


CHAPTER    XXIX 


THE    GENERAL    PRINCIPLES     AND    MECHANISM 
OF     INFECTION     AND     IMMUNITY 

Each  and  every  living  thing  must  feed,  assimilate  and  eliminate. 
Living  matter  cannot  continue  in  active  life  without  performing  these 
functions.  There  are  certain  resting  forms  in  which  these  functions 
are,  for  the  time,  held  in  abeyance.  Such  are,  eggs,  spores,  seeds  and 
reproductive  cells.  These  organisms  possess  only  potential  life;  they 
are  not  in  active  life.  A  grain  of  corn  or  wheat,  or  any  vegetable 
seed,  contains  a  germ  cell,  a  store  of  food  and  an  enzyme.  When 
placed  in  the  ground,  under  suitable  conditions  of  temperature  and 
moisture,  the  enzyme  begins  to  split  up  the  stored  food,  the  germ 
cells  begin  to  utilize  the  split  products  and  potential  life  awakens  into 
active  life.  The  revivified  germ  cell  is  now  able  to  feed  on  the  con- 
stituents of  the  soil,  the  stalk  grows  and  the  grain  or  seed  is  repro- 
duced. The  spores  of  anthrax  are  only  potentially  alive  and  active 
life  begins  anew  only  in  the  presence  of  proper  nutriment.  The 
granules  into  which  certain  other  bacteria  are  changed  in  the  absence 
of  food  are  further  examples  of  resting  forms.  Ova,  whether  those 
of  lower  or  higher  animals,  after  stimulation  by  the  spermatic  cells, 
and  under  proper  conditions,  begin  to  develop  into  active  life.  In  all 
cases  life  in  one  form  or  another  is  potentially,  at  least,  continuous. 

No  thing  in  active  life  remains  in  a  condition  of  equilibrium.  It 
absorbs,  assimilates  and  eliminates.  Metabolism  is  a  life  function 
and  there  can  be  no  active  life  without  it.  Indeed,  it  is  metabolism, 
active  and  latent,  that  distinguishes  between  living  and  dead  matter. 
When  matter  becomes  endowed  with  this  function,  it  is  no  longer 
dead,  but  is  alive.  Nothing  in  active  life  can  be  conceived  of  as  exist- 
ing alone.  It  must  have  food  or  die. 

The  morphologic  unit  of  life  is  the  cell,  although  the  physiologic 
unit  is  the  molecule  or  the  group  of  molecules  essential  to  the  celL 
All  living  things  are  essentially  proteins.  The  cell  may  contain  carbo- 


224  MECHANISM    OF    INFECTION    AND    IMMUNITY 

hydrates,  fats  and  extractives,  but  the  functions  of  life  reside  in  its 
protein  molecules.  Each  kind  of  life  must  consist  of  its  own  specific 
proteins  and  there  are  as  many  kinds  of  proteins  as  there  are  kinds 
of  cells.  It  follows  that  proteins  are  specific.  Those  of  the  colon 
bacillus  are  not  identical  with  those  of  the  typhoid  and  differ  more 
widely  still  from  those  of  the  tubercle  bacillus.  Relationship  between 
varieties  and  species  depends  on  similarity  in  the  chemical  constitution 
of  the  molecules.  The  essential  proteins  of  wheat  and  barley  are  not 
identical,  but  are  more  closely  related  in  chemical  structure  than  are 
those  of  barley  and  those  of  pumpkin  seed. 

All  cells,  so  long  as  they  are  in  active  life,  must  feed.  Otherwise, 
they  cannot  grow  and  multiply.  This  is  equally  true  of  cells  which 
have  an  individual  existence  and  constitute  unicellular  forms  of  life, 
and  of  those  which  have  a  communal  life  and  exist  in  the  organs  of 
multicellular  beings,  such  as  man.  A  living  cell  can  feed  only  on 
that  with  which  it  comes  in  contact.  Some  of  the  cells  of  man's  body, 
such  as  the  leukocytes,  can  go  in  quest  of  food,  while  others  are  fixed 
and  must  depend  on  what  is  brought  to  them. 

Each  cell  feeds  by  means  of  its  enzymes  which  split  up  the  pabulum 
into  blocks  which  can  be  fitted  into  its  molecular  structures.  Each  kind 
of  cell  must  have  its  own  specific  ferment  or  ferments  and  there  are 
as  many  kinds  of  ferments  or  enzymes  as  there  are  kinds  of  cells. 
There  are  enzymes  which  split  up  carbohydrates,  known  as*  diastases, 
and  those  which  split  up  fats,  known  as  lipases,  but  in  our  studies 
of  infection  and  immunity,  we  are  especially  concerned  with  those 
that  split  up  proteins,  known  as  proteases  or  proteolytic  enzymes  or 
ferments.  These  enzymes  are  specific  in  two  senses;  first  they  are 
products  of  specific  cells  and  second,  they  can  act  only  on  proteins  of 
certain  chemical  structure.  It  must  be  evident  that  a  cell  can  feed  only 
on  that  material  which  is  digestible  by  its  enzymes.  This  is  true  of 
single  cells  and  of  multiple  cells.  Horn  contains  proteins  and  other 
nitrogenous  substances,  but  man  cannot  live  on  it  because  the  enzymes 
of  his  alimentary  canal  cannot  digest  it.  Only  that  which  its  enzymes 
can  properly  prepare  for  assimiliation  is  food  for  the  organism, 
whether  it  be  unicellular  or  multicellular.  With  this  understanding 
of  the  conditions  under  which  cells  grow  and  multiply,  we  are  ready 


MECHANISM    OF    INFECTION    AND    IMMUNITY  225 

to  study  some  of  the  phenomena  of  infection.  In  doing  this  we  will 
confine  ourselves  to  bacteria. 

Bacteria. — There  are  some  widely  prevalent  views  concerning  bac- 
teria which  in  my  opinion  are  quite  erroneous.  It  is  generally  stated 
that  bacteria  are  low  forms  of  plant  life.  This  belief  is  founded  on 
an  early  observation  that  they  are  not  readily  soluble  in  dilute  acids 
or  alkalies.  Is  this  enough  to  justify  their  classification  as  plants?  Hair, 
skin  and  horn  are  not  readily  soluble  in  dilute  acid  or  alkali  and  still 
they  can  hardly  be  called  plants.  Plant  cells,  generally,  at  least,  con- 
tain cellulose;  bacteria  do  not.  Plants,  under  normal  conditions,  take 
in  carbonic  acid  and  give  off  oxygen ;  bacteria  absorb  oxygen  and  give 
off  carbonic  acid.  Many  think  that  bacteria  contain  no  nuclei,  because 
there  is  no  differentiation  in  staining,  but  it  should  be  remembered 
that  their  staining  properties  show  that  they  are  practically  wholly 
composed  of  nuclein.  Some  think  that  they  are  of  simple  chemical 
structure,  because  morphologically  they  are  simple.  I  and  my  students 
have  shown  that,  chemically,  bacteria  are  quite  as  complicated  and  as 
highly  developed  as  are  the  cells  of  man's  body.  Functionally,  they 
are  highly  developed.  It  is  important  to  hold  this  in  mind  in  studying 
the  contests  between  bacterial  and  body  cells,  which  so  often  end 
in  the  discomfiture  of  the  latter. 

Bacteria  live  and  multiply  through  the  activity  of  their  enzymes. 
Their  extracellular  enzymes  split  the  pabulum  within  their  reach  into 
proper  blocks  and  their  intracellular  enzymes  fit  these  blocks  into  the 
bacterial  molecule.  It  must  be  plain  that  a  bacterium,  whose  enzymes 
cannot  act  on  body  proteins,  cannot  infect  that  animal.  Such  a 
bacterium  may  grow  outside  the  animal  body,  feed  on  dead  material 
and  elaborate  a  poison  which  may  harm  the  animal.  Such  a  bacterium 
is  the  Bacillus  botulinus.  The  peptonizing  bacteria  of  milk  so  change 
the  milk  proteins  that  they  are  absorbed  through  the  intestinal  walls 
of  infants  and  are  further  digested  in  the  blood  and  tissues  with  the 
formation  of  poisons  which  cause  the  symptoms  and  lesions  of  cholera 
infantum  and  the  other  diarrheal  diseases  of  infancy.  During  intra- 
uterine  life,  all  the  processes  of  digestion  are  parenteral,  that  is,  they 
do  not  occur  in  the  intestine  but  in  the  blood  and  tissues.  In  infancy, 
the  walls  of  the  intestine  are  easily  permeable  and  parenteral  digestion 


226  MECHANISM    OF    INFECTION    AND    IMMUNITY 

continues,  especially  when  the  food  proteins  are  altered  by  bacterial 
growth.  In  rare  cases  of  summer  diarrhea,  casein,  but  little  altered, 
has  been  detected  in  the  blood  by  biologic  tests.  Bacteria  which  cause 
disease  by  the  elaboration  of  toxins  or  poisons  in  foods  before  they 
are  taken  into  the  body  are  known  as  toxicogenic  organisms.  This  term 
was  proposed  by  me  many  years  ago. 

Body  Cells. — These  live,  like  the  bacterial  cells,  by  means  of  their 
enzymes  which  also  are  extracellular  and  intracellular.  The  former 
cleave  the  pabulum  properly  and  the  latter  fit  the  blocks  into  the  mole- 
cules. The  feeding  cells  are  not  confined  to  the  leukocytes.  All  the 
living  cells  of  the  body,  so  long  as  they  are  alive,  feed.  They  eat, 
assimilate  and  eliminate.  In  the  higher  animals,  including  man,  the 
gross  digestion  for  the  whole  is  done  in  the  alimentary  canal.  This  is 
known  as  enteral  digestion.  The  special  preparation  of  food  for  the 
cells  of  the  different  organs,  however,  is  done  by  their  own  specific 
enzymes  and  this  process  is  known  as  parenteral  digestion.  Moreover, 
occasionally,  proteins  in  small  amounts  pass  from  the  alimentary  canal 
into  the  lymph  and  blood  without  complete  digestion.  Fine  bits  of 
organic  matter  are  inhaled  and  find  their  way  into  the  system  without 
being  subjected  to  any  form  of  enteral  digestion.  Finally,  and  of 
the  greatest  importance  in  the  present  study,  living  proteins,  known 
as  bacteria,  find  their  way  into  the  tissues.  These  not  only  have 
escaped  enteral  digestion,  but  they  are  capable  of  growth  and  multi- 
plication, and  if  their  development  in  the  body  be  prevented  it  must 
be  through  parenteral  digestion.  Whether  they  are  engulfed  by  phago- 
cytes or  destroyed  by  the  fluids,  it  is  in  either  case  parenteral  digestion. 
It  must  be  evident  that  parenteral  digestion  is  the  big  and  deciding 
factor  in  most  cases  of  infection.  If  it  fails  or  if  it  is  slow  in  pro- 
cedure, the  invading  bacteria  may  multiply.  If  it  proceeds  promptly 
and  efficiently  the  invaders,  which  under  natural  conditions  are  few 
in  number,  are  destroyed  before  they  can  multiply  and  the  body  is 
protected.  Now,  we  have  the  great  problem  of  infection  and  immunity 
fairly  before  us.  It  is  a  contest  between  bacterial  and  body  cells  and, 
as  we  have  seen,  they  are  armed  with  similar  weapons.  The  bacterial 
cells  have  their  enzymes,  poisons  and  toxins.  The  body  cells  have 
their  enzymes,  bactericidal  and  bacteriolytic  agents,  opsonins,  and 
phagocytes.  The  phagocytes  constitute  the  mobile  army  of  defense 


MECHANISM    OF    INFECTION    AND    IMMUNITY  227 

and  the  fixed  cells  elaborate  destructive  weapons.  Which  of  these 
bears  the  brunt  of  the  defense  depends  on  the  armament  of  the  invader. 
Whether  a  given  bacterium  is  pathogenic  to  a  given  animal  or 
not,  depends  essentially  on  two  things.  First,  can  it  feed  on  the  pro- 
teins of  that  animal's  body  ?  If  it  cannot,  it  can  do  no  harm.  Secondly, 
can  the  cells  of  the  body  destroy  the  invading  cells  before  they  can 
multiply  ? 

The  Phenomena  of  Infection. — It  should  be  clearly  understood 
that  only  a  living  thing  can  infect.  It  must  not  only  be  alive,  but  it 
must  be  able  to  multiply  in  the  animal  body.  It  is  true  that  the  injec- 
tion of  diphtheria  or  tetanus  toxin  into  an  animal  may  cause  all  the 
symptoms  and  lesions  of  disease,  but  this  is  an  artificial  procedure,  and, 
besides,  the  toxin  is  the  product  of  bacterial  growth.  An  infectious 
disease  arises  when  foreign  cells  find  their  way  into  the  body  and 
multiply  to  the  detriment  of  the  body  cells.  Simply  carrying  virulent 
bacteria  on  the  surface  or  in  the  cavities  of  the  body  does  not  constitute 
infection.  It  is  not  rare  to  find  tubercle  bacilli  on  the  hands  of  those 
who  care  for  others  ill  of  this  disease.  According  to  Fliigge,  70  per 
cent,  of  those  in  houses  where  there  is  a  case  of  epidemic  meningitis 
carry  the  organisms.  In  a  schoolroom  in  which  a  child  has  developed 
diphtheria,  30  per  cent,  of  all  the  children  may  have  the  diphtheria 
bacillus  in  their  throats  and  are  not  infected.  In  order  to  develop 
infection,  the  bacterium  must  feed  on  the  body.  Carriers  of  infection 
are  of  importance  to  the  epidemiologist,  but  they  are  not  necessarily 
infected.  The  bacterium  must  not  only  feed  on  the  animal  tissue,  but 
it  must  multiply.  The  essential  difference  between  saprophytic  and 
pathogenic  bacteria  is  that  the  latter  can  multiply  in  the  animal  body, 
while  the  former  cannot.  Saprophytic  bacteria  contain  in  their  cellular 
substance  just  as  much  protein  poison  as  the  pathogenic  organisms 
do  and  it  is  easy  to  kill  an  animal  by  injecting  a  relatively  large  amount 
of  them  into  the  abdominal  cavity,  but  this  is  not  infection.  A  bacterium 
is  not  pathogenic  to  a  given  animal  unless  it  can  convert  that  animal's 
proteins  into  its  own  proteins. 

Saprophytic  bacteria  are  speedily  digested  by  the  enzymes  in  the 
blood  and  tissues  of  the  body,  and  if  they  be  injected  in  large  amount 
the  protein  poison  set  free  may  be  sufficient  to  quickly  kill  the  animal. 


228  MECHANISM    OF    INFECTION    AND    IMMUNITY 

So  great  is  the  bacteriolytic  action  of  the  blood  that  even  some  patho- 
genic bacteria  do  not  infect  when  injected  directly  and  wholly  into 
the  blood.  This  is  true  of  the  bacillus  of  symptomatic  anthrax.  A 
dose  which  infects  when  administered  subcutaneously,  fails  when  given 
intravenously.  The  cholera  bacillus  is  harmless  when  introduced  sub- 
cutaneously in  doses  which  would  infect  by  the  intestine.  In  the  first 
instance,  it  is  speedily  killed  by  the  bactericidal  constituents  of  the 
tissues ;  in  the  second  it  grows  and  multiplies  in  the  intestine  in  which 
it  does  not  come  in  contact  with  the  germicidal  agents. 

There  are  many  conditions  which  influence  the  capability  of  bac- 
terial growth  in  the  animal  body.  A  given  bacterium  may  be  patho- 
genic to  one  species  of  animal  and  without  effect  on  another.  Some 
are  active  in  mixed  cultures,  one  bacterium  being  of  assistance  to 
another.  Some  grow  in  certain  tissues  of  the  body  and  not  in  others. 
The  number  of  bacteria  introduced  into  the  animal  is  an  important 
factor.  One  anthrax  bacillus  may  kill  a  mouse  and  one  tubercle 
bacillus  may  have  a  like  effect  on  a  guinea-pig,  but  these  are  exceptions, 
and  whether  or  not  an  infection  results  depends,  in  most  instances,  in 
part,  on  the  number  and  virulence  of  the  organisms  introduced. 

While  the  blood  has  a  marked  bactericidal  action  on  some  bacteria, 
it  forms  an  excellent  culture-medium  for  others.  Virulent  streptococci, 
plague  and  tubercle  bacilli  grow  abundantly  in  the  blood  and  kill  the 
more  promptly  the  sooner  they  find  their  way  into  the  circulation.  Quite 
naturally,  many  bacteria  grow  most  vigorously  in  injured  and  necrotic 
tissue  on  account  of  the  lessened  resistance.  The  readiness  with  which 
streptococci  take  possession  of  tissues  already  weakened  by  cancer, 
tuberculosis  or  syphilis  is  an  illustration. 

Incubation. — The  period  of  incubation  of  an  infectious  disease  is 
the  time  interval  between  the  introduction  of  the  infecting  agent 
and  the  first  appearance  of  the  symptoms  of  the  disease.  This  varies 
greatly  in  different  diseases  and  for  the  same  diseases  in  different 
animals.  With  the  same  disease  in  the  same  species  there  are  also 
variations,  but  not  so  marked.  For  instance,  one  swallows  typhoid 
bacilli,  he  does  not  develop  fever  the  same  day  or  the  next,  but  as  a 
rule  between  the  sixth  and  tenth  day.  In  some  individuals  the  period 
of  incubation  for  this  disease  may  be  longer.  During  this  period 


MECHANISM    OF    INFECTION    AND    IMMUNITY  229 

there  is  no  recognizable  disturbance  in  the  health  of  the  individual, 
either  subjectively  or  objectively.  He  considers  himself  well  and 
attends  to  his  usual  duties,  and  yet  this  is  an  important  and  critical 
time  in  the  development  of  the  infection.  The  bacilli  are  growing  and 
multiplying  enormously  in  the  man's  body.  They  are  converting  body 
proteins  into  bacterial  proteins,  native  into  foreign  proteins,  and  this 
goes  on  without  the  host  being  conscious  of  it.  The  ferments  of  the 
bacterial  cells  are  fitting  the  body  proteins  into  the  cellular  molecules 
of  the  bacteria.  During  the  period  of  incubation,  the  bacterial  cells 
supply  the  enzymes,  the  body  proteins  constitute  the  substrate,  the 
process  is  synthetic  and  constructive,  no  poison  is  set  free  and  conse- 
quently no  symptoms  are  manifest.  It  follows  that  the  multiplication 
of  the  typhoid  bacillus  in  man's  body  is  not  the  direct  cause  of  the 
symptoms  of  the  disease.  There  is  no  evidence  that  the  growth  and 
multiplication  of  the  bacilli  proceed  at  the  expense  of,  or  directly 
cause  injury  to,  body  cells.  The  bacilli  feed  on  the  simple,  soluble 
proteins  of  the  body.  A  tubercle  bacillus  passes  through  the  intestinal 
wall  and  leaves  no  lesion.  A  plague  bacillus  may  penetrate  the  skin 
of  an  animal  and  make  no  visible  alteration.  The  rate  at  which  the 
virus  multiplies  during  the  period  of  incubation  is  an  important  factor 
in  determining  the  final  outcome.  The  more  virulent  the  virus,  the 
more  rapidly  does  it  multiply,  and  this  means  a  larger  amount  of 
body  protein  converted  into  bacterial  protein.  The  phenomena  of  the 
period  of  incubation  may  be  studied  in  a  guinea-pig  into  the  abdominal 
cavity  of  which  a  fatal  dose  of  a  virulent  culture  of  the  colon  bacillus 
has  been  injected.  In  this  experiment  the  incubation  period  is  from 
eight  to  twelve  hours,  during  which  time  the  infected  animal  is  in  its 
behavior  undistinguishable  from  its  untreated  fellows.  However,  if 
a  drop  of  the  abdominal  fluid  be  taken  out  from  hour  to  hour  it  will 
be  seen  that  the  bacilli  are  multiplying  rapidly. 

The  Disease. — In  some  cases  the  period  of  incubation  passes 
abruptly,  in  others  more  gradually,  into  that  of  the  active  disease. 
Symptoms,  both  subjective  and  objective,  develop  and  indicate  a  more 
or  less  marked  departure  from  health.  In  some  diseases  there  is  a 
chill,  which  may  vary  greatly  in  severity,  and  this  is  followed  by 
fever.  Evidently  something  has  happened  which  disturbs  physiologic 


230  MECHANISM    OF    INFECTION    AND    IMMUNITY 

processes.  The  body  cells  have  begun  the  contest  against  the  invaders. 
Since  the  invasion  began  they  have  been  preparing  for  the  war  and 
now  the  battle  has  begun.  The  bacilli  have  gained  entrance  and  multi- 
plied at  the  expense  of  the  soluble  proteins  of  the  body  because  the 
animal  cells  were  not  at  first  prepared  to  combat  them.  Now  they  have 
developed  bactericidal  and  bacteriolytic  ferments  and  opsonins,  possibly 
antitoxins,  and  with  these  the  further  development  of  the  bacteria  is 
to  be  contested.  When  the  infecting  organism  is  a  toxin  producer,  like 
the  diphtheria  or  tetanus  bacillus,  it  is  not  the  cellular  substance  of 
the  bacteria  which  directly  and  immediately  endangers  the  body  cells, 
so  much  as  its  soluble  product,  the  toxin.  In  this  case,  the  contest  is 
decided  by  the  ability  of  the  body  cells  to  elaborate  and  make  available 
enough  antitoxin  to  neutralize  the  bacterial  toxin.  In  this  case,  the 
therapeutic  administration  of  antitoxin  has  secured  to  curative  medi- 
cine its  greatest  triumph,  and  success  or  failure  depends  on  the  early 
administration  of  this  magical  cure  in  sufficient  amount.  The  cells 
of  the  horse  have  been  trained  to  produce  this  body  and  now  it  is 
poured  into  the  blood  current  of  the  child  to  save  its  cells  from  destruc- 
tion. The  diphtheria  bacilli  contain  a  cellular  poison,  quite  different 
from  the  toxin,  but  since  the  bacilli,  except  in  small  numbers,  are  not 
in  the  child's  blood  and  tissue,  but  in  its  throat,  the  cellular  poison 
may  be  neglected,  for  as  a  rule  the  few  in  the  body  do  not  contain 
enough  poison  to  endanger  the  life  of  the  child.  Cure,  then,  depends 
on  the  neutralization  of  the  toxin  before  it  has  done  irreparable  harm. 
When  the  infecting  bacterium  is  one  best  combated  by  phagocytes, 
the  body  cells  supply  opsonins  which,  in  some  way  yet  unknown,  ren- 
der the  invaders  less  resistant  to  the  leukocytes.  In  these  cases,  the 
result  depends  on  the  effectiveness  with  which  both  the  fixed  and 
mobile  cells  of  the  body  perform  their  functions.  One  of  the  important 
factors  is  the  number  as  well  as  the  virulence  of  the  invading  bacteria 
at  the  time  when  the  contest  begins.  The  greater  the  number,  the  more 
must  the  phagocytes  devour,  and  feeding  is  a  limited  function.  The 
more  virulent  they  are,  the  less  effective  will  be  the  opsonins.  Rosenow 
has  shown  that  the  opsonins  are  not  effective  against  the  more  virulent 
strains  of  streptococci  and  that  infection  with  these  generally  proves 
fatal.  It  is  worthy  of  note  that  bacteria  devoured  by  phagocytes  do 
not  endanger  the  life  of  their  host  to  the  extent  and  in  the  same  way 


MECHANISM    OF    INFECTION    AND    IMMUNITY  231 

as  do  those  which  suffer  extracellular  digestion.  In  the  latter  instance, 
the  cellular  poison  of  the  bacteria  is  set  free  and  in  its  death  it  becomes 
most  dangerous  to  its  host. 

By  far  the  larger  number  of  bacteria  which  infect  man  do  not 
elaborate  soluble  toxins  and  for  these  we  can  have  no  antitoxin.  Of 
the  other  pathogenic  bacteria  there  are  many  which,  in  first  infections 
at  least,  are  not  to  any  large  extent  devoured  by  phagocytes.  The 
members  of  this  large  class,  which  cannot  be  met  with  antitoxins  or 
disposed  of  by  stimulated  phagocytosis,  must  be  dealt  with  by  bacteri- 
cidal and  bacteriolytic  enzymes.  The  potent  poison  which  they  con- 
tain is  set  free  and  exerts  its  deleterious  effect,  which  is  determined 
by  the  rapidity  with  which  the  bacterial  cells  are  disrupted.  It  must 
be  evident  that  the  development  of  powerful  bacteriolytic  enzymes  at 
a  time  when  the  body  is  filled  with  bacteria  would  be  most  disastrous. 
The  faster  the  invaders  are  destroyed,  the  more  danger  is  there  to 
the  host.  This  is  well  illustrated  in  typhoid  fever,  in  which  the  bacillus 
produces  no  soluble  toxin  and  consequently  there  can  be  no  antitoxin 
developed  and  in  which  there  is  no  increase  in  the  phagocytes.  The 
greatest  misfortune  that  happens  in  the  progress  of  typhoid  fever  is 
the  rapid  development  of  a  powerful  bacteriolytic  enzyme  and  the 
speedy  destruction  of  the  invading  bacteria  in  large  numbers.  This  is 
true  of  plague  and  typhus,  as  well  as  of  typhoid  fever.  It  does  not 
apply  to  diseases  due  to  soluble  toxins,  such  as  diphtheria  and  tetanus, 
and  probably  not  to  those  combated  exclusively  by  phagocytes,  if  there 
be  such. 

The  assertion  has  been  made  that  the  infectious  diseases  have  bene- 
fited the  race  by  the  destruction  of  the  unfit.  This  idea  I  have  com- 
bated most  vigorously  since  our  study  of  typhoid  fever  in  the  army 
in  1898.  My  colleagues  and  I  found  that  out  of  9,481  soldiers  who 
had  previously  been  on  the  sick  report  and  could  not  be  regarded  as 
possessing  standard  health,  648,  or  6.8  per  cent.,  contracted  typhoid 
fever;  whereas,  out  of  46,383  men  who  had  no  preceding  illness,  7,197, 
or  15.3  per  cent.,  developed  typhoid  fever.  More  than  90  per  cent,  of 
the  men  who  developed  typhoid  had  no  preceding  intestinal  disorder. 

Under  ordinary  conditions  the  strong,  busy  man,  especially  the 
one  whose  activities  demand  wide  excursions  from  his  home,  is  more 
likely  to  become  infected  than  the  one  whose  sphere  of  action  is  more 


232  MECHANISM    OF    INFECTION    AND    IMMUNITY 

limited  on  account  of  infirmity.  The  reason  for  this  is  too  obvious  to 
need  statement,  and  it  follows  that  more  men  than  women  and  more 
adults  than  children  have  typhoid  fever.  Moreover,  the  case  mortality 
is  greater  among  the  strong,  because  death  in  this  class  of  infectious 
diseases  is  often  due  to  the  rapidity  with  which  the  invading  organism 
is  broken  up  by  the  secretions  of  the  body  cells  and  the  protein  poison 
made  effective.  From  this  I  have  concluded  that  contagion,  like  war, 
destroys  the  very  flower  of  the  race.  This  view  is  sustained  by  the 
historians  of  the  pestilences  of  former  times. 

Thucydides,  in  his  description  of  the  plague  at  Athens,  says: 
"Moreover,  no  constitution,  whether  in  respect  of  strength  or  weakness, 
was  found  able  to  cope  with  it ;  nay,  it  swept  away  all  alike,  even  those 
attended  to  with  the  most  careful  management."  Procopius,  in  his 
account  of  the  Justinian  epidemic,  states  that  youth  was  the  most 
perilous  season,  and  females  were  less  susceptible  than  males.  Cogan, 
in  describing  an  outbreak  of  typhus  at  Oxford  in  1577,  writes:  "The 
same  kind  of  ague  raged  in  a  manner  over  all  England  and  took  away 
very  many  of  the  strongest  sort,  and  in  their  lustiest  age,  and  for  the 
most  part,  men,  and  not  women  and  children,  culling  them  out  here 
and  there,  even  as  you  would  choose  the  best  sheep  of  a  flock."  In 
his  account  of  the  plague  of  1665  in  London,  Boghurst  makes  the 
following  statement: 

Of  all  the  common  hackney  prostitutes  of  Luteners-lane,  dog-yard,  cross- 
lane,  Baldwins-gardens,  Hatton-gardens  and  other  places,  the  common  criers 
of  oranges,  oysters,  fruits,  etc.,  all  the  impudent  drunken,  drubbing  bayles  and 
fellows  and  many  others  of  the  rouge  route,  there  is  but  few  missing  —  verify- 
ing the  testimony  of  Diemerbroech  that  the  plague  left  the  rotten  bodies  and 
took  the  sound. 

Like  testimony  comes  from  an  account  of  the  plague  at  Moscow: 
"Drunkards  and  persons  of  feeble  temperament  were  less  subject  to 
attack."  Davidson  observed  that  typhus  fever  was  more  frequent 
among  the  robust  than  the  weak.  He  states  that  out  of  429  cases,  the 
spare  and  unhealthy  taken  together  made  only  about  17  per  cent.  He 
adds  that  the  death-rate  among  the  poor  was  one  in  twenty-three,  while 
among  the  well  to  do,  it  was  one  in  four.  The  greater  mortality  of 
typhus  among  the  higher  classes  has  been  noted  by  Barber  and  Cheyne 
and  by  Braken.  Hurty,  nearly  a  century  ago,  wrote :  "A  fever  which 


MECHANISM    OF    INFECTION    AND    IMMUNITY  233 

consigns  thousands  to  the  grave,  consigns  tens  of  thousands  to  a 
worse  fate — to  hopeless  poverty,  for  fever  spares  the  children  and 
cuts  off  the  parents,  leaving  the  wretched  offspring  to  fill  the  future 
ranks  of  prostitution,  mendicancy  and  crime."  Creighton  says : 

The  best  illustrations  of  the  greater  severity  and  fatality  of  typhus  among 
the  well  to  do  come  from  Ireland  in  times  of  famine,  and  will  be  found  in 
another  chapter.  But  it  may  be  said  here,  so  that  this  point  in  the  natural 
history  of  typhus  may  not  be  suspected  of  exaggeration,  that  the  enormously 
greater  fatality  of  typhus  (of  course,  in  a  smaller  number  of  cases)  among 
the  richer  classes  of  the  Irish  families,  who  had  exposed  themselves  in  the 
work  of  administration,  of  justice,  or  of  charity,  rests  on  the  unimpeachable 
authority  of  such  men  as  Graves,  and  on  the  concurrent  evidence  of  many. 

In  the  active  stage  of  disease  due  to  bacterial  invasion  of  the  body, 
the  body  cells  supply  the  ferment,  the  bacterial  cells  constitute  the 
substrate;  the  process  is  essentially  destructive  and  analytic;  complex 
cellular  proteins  are  split  into  simple  soluble  bodies ;  the  protein  poison 
is  set  free,  exerts  its  deleterious  effects  on  the  body  cells  and  disturbs 
the  health ;  the  evidence  of  infection  rises  to  the  plane  of  clinical  obser- 
vation; the  symptoms  of  the  disease  become  manifest  and  the  contest 
between  bacterial  and  animal  cells  continues  until  one  or  the  other 
holds  possession. 

It  should  not  be  understood  that  there  is  always  a  sharp  line  of 
demarcation  between  the  period  of  incubation  and  the  appearance  of 
active  disease.  The  bacterial  growth  may  be  extending  into  new  parts 
of  the  body  coincidently  with  its  destruction  in  other  regions. 

Fever. — All  bacteria  are  capable  of  inducing  fever,  and  this  is  a 
most  constant  accompaniment  of  infection.  Fever  is  not  directly  due 
to  the  growth  of  bacteria  in  the  body.  It  is  not  in  evidence  during 
the  period  of  incubation  when  bacterial  growth  is  most  abundant.  The 
early  progress  of  tuberculosis  is  without  fever,  because  at  this  time 
the  number  of  bacilli  in  the  body  is  few  and  most  of  these  are  living. 
It  is  not  until  the  body  becomes  sensitized  against  the  invading  organ- 
ism and  begins  to  digest  and  destroy  it  that  fever  makes  its  appear- 
ance. The  face  may  be  covered  with  acne  pustules,  each  of  which  con- 
tains streptococci,  and  still  there  is  no  elevation  of  temperature, 
because  the  cocci  are  not  reached  and  digested  by  the  bacteriolytic 
enzymes  of  the  blood  and  lymph.  The  fever  of  infection  results  from 
the  parenteral  digestion  of  the  bacterial  proteins. 


234  MECHANISM    OF    INFECTION    AND    IMMUNITY 

Many  years  ago  Gamaleia  showed  that  fever  follows  the  parenteral 
introduction  of  dead  as  well  as  living  bacteria,  either  pathogenic  or 
non-pathogenic.  He  concluded  that  fever  is  not  a  phenomenon  of 
bacterial  growth  in  the  body.  Furthermore,  he  found  that  the  less 
virulent  the  organism,  the  higher  and  more  persistent  is  the  fever.  A 
rabbit  inoculated  with  the  anthrax  bacillus  suffers  a  fever  for  only  a 
few  hours,  when  the  temperature  falls  and  death  results,  while  one 
inoculated  with  a  highly  attenuated  anthrax  culture  (the  second  vac- 
cine) shows  fever  for  three  days  and  then  recovers.  With  a  highly 
virulent  culture,  there  may  be  but  little  or  no  elevation  of  temperature 
and  death  comes  within  from  five  to  seven  hours  after  inoculation. 
The  febrile  process  is  not  a  result  of  the  activity  of  the  bacteria,  but, 
on  the  contrary,  is  due  to  a  reaction  of  the  body  against  their  presence 
and  marks  their  destruction. 

More  recently  it  was  shown  by  experiments  in  my  laboratory  that 
fever  can  be  induced  in  animals  by  the  subcutaneous  injection  of  pro- 
teins of  diverse  origin  and  structure,  and  that  by  modifying  the  size 
and  frequency  of  the  dose,  the  type  of  fever  can  be  determined  at  will. 
By  injecting  egg-white  into  rabbits  and  by  regulating  the  size  and 
interval  between  doses,  one  may  induce  an  intermittent,  remittent, 
continued  or  acute  fever.  In  the  last  mentioned,  the  temperature  can 
be  carried  to  107  F.  with  a  fatal  termination.  Not  only  fever  but 
its  accompaniments  also  may  be  developed.  In  the  continued  fever 
thus  induced,  there  is  the  morning  fall  and  the  evening  rise  so  con- 
stantly seen  in  typhoid.  There  is  loss  of  appetite  with  lassitude, 
gradual  emaciation,  decreased  urinary  output  and  increased  nitrogen 
elimination.  Protein  fever,  which  includes  all  infective  and  practically 
all  clinical  fevers,  results  from  parenteral  digestion.  In  this  process 
the  animals'  cells  supply  the  ferment  and  the  foreign  protein  constitutes 
the  substrate.  The  foreign  protein  may  enter  the  body  living  or  dead, 
with  or  without  form.  It  may  be  detached  and  dead  tissue  from 
the  animal's  body,  as  after  burns.  It  may  be  absorbed  from  some 
mucous  surface,  as  in  hay  fever.  It  may  be  artificially  introduced, 
as  in  serum  disease.  It  is  usually  a  living  protein,  as  in  the  infectious 
diseases. 

There  are  other  causes  of  fever,  but  that  of  the  infectious  diseases 
results  from  the  parenteral  digestion  of  the  infecting  agent  by  specific 


MECHANISM    OF    INFECTION    AND    IMMUNITY  235 

secretions  elaborated  by  the  body  cells.  It  is  a  phenomenon  of  the 
disposal  of  foreign  and  harmful  material  and  it  must  be  recognized 
as  beneficent.  However,  there  is  a  point  above  which  it  becomes  a 
danger  per  se.  In  parenteral  digestion,  the  following  sources  of  heat 
production  must  be  evident:  1.  The  unaccustomed  stimulation  and 
consequent  increased  activity  of  the  cells  which  supply  the  enzyme 
must  be  the  source  of  no  inconsiderable  increase  in  heat  production. 

2.  The  cleavage  of  the  foreign  protein  increases  the  heat  liberation. 

3.  The  reaction  between  the  digestive  products  and  the  tissues  leads 
to  increased  heat  production.     I  regard  the  first  and  third  as  the 
important  sources  of  the  overproduction  of  heat  in  the  infectious 
diseases. 

There  are  many  conditions  affecting  the  course  of  a  fever  and 
some  of  these  may  be  mentioned.  Some  viruses  sensitize  more  quickly 
and  thoroughly  than  others.  It  is  possible  that  the  living  bacterial 
cells,  so  long  as  they  are  living,  do  not  sensitize.  Some  of  the  bacterial 
protein  must  pass  into  solution  before  cell  penetration,  which  seems 
essential  to  thorough  sensitization,  can  occur.  A  living  colon  bacillus 
of  not  more  than  twenty-four  hours'  growth,  when  injected  intra- 
abdominally  in  a  guinea-pig,  requires  about  ten  hours  to  sensitize. 
With  dead  bacilli  the  time  is  reduced  to  half,  while  with  old  autolyzed 
cultures,  in  which  the  sensitizing  group  is  already  in  solution,  the  time 
is  further  shortened.  Some  pathogenic  bacteria,  like  the  tubercle 
bacillus,  have  been  so  long  parasitic  that  they  have  learned  to  protect 
themselves  by  deposits  of  fats  and  waxes.  Others  form  capsules  which 
serve  a  like  purpose.  In  this  way  they  are  probably  protected  to  some 
extent  against  the  destructive  enzymes  elaborated  by  the  body  cells. 
In  all  the  infectious  diseases,  the  destruction  of  the  invading  organism 
is  modified  and  delayed  by  the  altered  relation  between  ferments  and 
substrate  and  the  accumulation  of  fermentative  products.  The  blood 
is  a  highly  active  digestive  fluid  with  a  finely  adjusted  balance  between 
ferment  and  anti  ferment,  which  will  soon  be  better  understood  and 
the  solution  of  this  problem  will  add  another  triumph  to  scientific 
medicine.  When  the  ferment  in  the  blood  is  suddenly  activated, 
immediate  death  results,  as  is  seen  in  anaphylactic  shock.  When 
properly  regulated,  this  delicate  mechanism  protects  against  harmful 
bodies,  both  those  introduced  from  without  and  those  generated  within. 


INDEX 


Agglutination     201 

factors     202 

history     201 

Agglutinin      202 

Alexins     217 

Amboceptor     218 

Anthrax      77 

avenues  of  infection 85 

bacillus     80 

history     77 

symptomatic     127 

symptomatic,    bacillus 127 

symptomatic,     history 127 

Bacteria     27,  225 

antagonism   between    28 

capsules    of 16 

flagella    of 30 

metabolism     32 

morphology    of 27 

multiplication     28 

oxygen   need  of 30 

pathogenicity     33 

spore    formation 27 

structure    31 

symbiosis    of 29 

Body   cells 226 

Botulism     137 

bacillus     138 

history     137 

Cells,    body 226 

Cholera,     Asiatic 57 

bacillus     58 

history     57 

sources   of  infection 62 

Death-rates    from    infectious    diseases 14 

Disease,    theories    concerning 19 

Diphtheria     167 

antitoxin     170 

bacillus     168 

history    167 

Dysentery    87 

Flexner     bacillus 89 

history     87 

Shiga     bacillus 88 

sources   of   infection 91 

Edema,     malignant 131 

bacillus     131 

history     131 

Endolysis    216 

Eye  as  portal  of  entrance  for  bacteria 35 

Fever    of  infection 233 

Gas  phlegmon 132 


Germ   theory 23 

Germicidal    sera 213 

Glanders     133 

avenues  of  infection 134 

bacillus    134 

history     133 

Immune    sera 219 

Immunity     177 

acquired,  phagocytosis  in 192 

and  infection,  mechanism  of 223 

natural,  phagocytosis  in 188 

Incubation  period  of  infection 228 

Infection  and   immunity,  mechanism  of .  . .   223 

avenues    of 35 

fever  of 233 

phenomena  of 227 

Infectious  diseases,  death-rates  from 14 

disease,  incubation  period 228 

Intestines   as    portal   of    entrance    for    bac- 
teria          37 

Koch,  work  of 25 

Leprosy     51 

avenues  of  infection 54 

bacillus   53 

history     of 51 

present  distribution 52 

Lungs  as  portal  of  entrance  for  bacteria.  .      36 

Malta  fever 139 

history     139 

organism     139 

Miasm,    theory   of 22 

Mouth  as  portal  of  entrance  for  bacteria.  .      35 

Normal    sera 213 

Nose  as  portal  of  entrance  for  bacteria.  . .      35 

Opsonins     207 

Pasteur,   work   of 24 

Phagocytosis    183 

in  acquired   immunity    192 

in  injuries  and   disease 193 

in  natural  immunity 188 

Plague    Ill 

bacillus   117 

history     Ill 

mode    of    infection 121 

Pneumonia     143 

bacillus   144 

history     143 

Precipitate    199 

Precipitinogen     197 

Precipitins   , 198 

specific    197 

specific,    history    197 


238 


INDEX 


Pseudotuberculosis     49 

Sausage  Poisoning:  see  Botulism 137 

Sera,     germicidal 213 

immune     219 

normal    213 

Skin  as  portal  of  entrance  for  bacteria...  35 

Staphylococcic     infection 161 

infection,    organism 161 

Stomach  as  portal  of  entrance  for  bacteria.  37 

Streptococcic   infection 153 

infection,   history 153 

infection,    organism 154 

Tetanus    149 

bacillus   149 

history     149 


Tuberculosis  39 

avenues  of  infection 47 

avian  type  of 44 

bacillus  40 

bovine  bacillus  42 

history  39 

piscidian  variety  of 45 

pseudotuberculosis 49 

sources  pf  infection 48 

Typhoid  fever 65 

history  65 

sources  of  infection 70 

Typhus  fever 93 

history 93 

organism  103 

transmission  .  .  106 


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